WO2022177302A1 - Pyrimidine-fused ring compound with dna-pk inhibition activity and use thereof - Google Patents

Pyrimidine-fused ring compound with dna-pk inhibition activity and use thereof Download PDF

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Publication number
WO2022177302A1
WO2022177302A1 PCT/KR2022/002310 KR2022002310W WO2022177302A1 WO 2022177302 A1 WO2022177302 A1 WO 2022177302A1 KR 2022002310 W KR2022002310 W KR 2022002310W WO 2022177302 A1 WO2022177302 A1 WO 2022177302A1
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Prior art keywords
methyl
amino
tetrahydro
pyran
alkyl
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PCT/KR2022/002310
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French (fr)
Korean (ko)
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이희진
박진영
이혜미
양덕모
남은혜
김학도
정희진
정원근
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보령제약 주식회사
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Publication of WO2022177302A1 publication Critical patent/WO2022177302A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

Definitions

  • the present invention relates to pyrimidine-fused ring compounds having DNA-PK inhibitory activity and uses thereof.
  • DNA is constantly damaged by metabolic or environmental factors. In this case, the normal state can be restored through the DNA repair mechanism in most cases, but otherwise, mutations may occur, resulting in cell death or cancer.
  • the main causes of DNA damage include reactive oxygen species formed as a by-product of oxidative metabolism, ionizing radiation for anticancer treatment, and use of anticancer drugs such as bleomycin.
  • DSB DNA double strand break
  • NHEJ non-homologous end-joining
  • HR homologous recombination
  • NHEJ is a mechanism that directly connects the ends of cleaved DNA double-stranded, and occurs at all stages of the cell cycle, where DNA-dependent protein kinase (DNA-PK) plays a key role.
  • DNA-PK is a nuclear serine/threonine protein kinase complex consisting of the catalytic subunit DNA-PKcs and a heterodimer of Ku protein (Ku70/Ku80). After the Ku70/Ku80 heterodimer recognizes and binds to the cleaved DNA end, DNA-PKcs are recruited to form an activated complex (Yoo S et al., Nucleic Acids Res 1999; 27: 4679-4686).
  • DNA-PK inhibitors can induce cell death without repairing DNA-damaged cells by interfering with NHEJ, various therapeutic effects related to DNA damage can be expected.
  • the DNA-PK inhibitors NU7026 and KU-0060648 have been reported to be able to potentiate the cytotoxicity of topoisomerase II inhibitors (Willmore et al., Blood 2004; 103: 4659-4665, Munck et al. ., Mol Cancer Ther 2012; 11: 1789-1798), NU7441 potentiated the effect of ionizing radiation in a breast cancer model (Ciszewski et al., Breast Cancer Res Treat 2014; 143: 47-55).
  • DNA-PK inhibitors have been shown to be effective as single agents against tumors with high levels of replication stress, such as ATM-deficient lymphoma (Riabinska et al., Science Translational Medicine 2013; 189: 189ra78).
  • An object of the present invention is to provide a pyrimidine-fused ring compound having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the pyrimidine-fused ring compound.
  • Another object of the present invention is to provide a pharmaceutical use of the pyrimidine-fused ring compound, specifically, a pharmaceutical composition for treating or preventing a DNA-PK-related disease comprising the pyrimidine-fused ring compound as an active ingredient, To provide a method for treating or preventing a DNA-PK-related disease using the compound, or a method for treating or preventing a DNA-PK-related disease, comprising administering the compound.
  • the present invention was completed by confirming that the pyrimidine-fused ring compounds represented by Chemical Formula 1 mentioned below inhibit DNA-PK activity.
  • the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • n 0, 1 or 2;
  • X 1 is NR 1 or CR 2 R 3 ⁇ wherein is a double bond, then R 1 or R 3 is nothing (null) ⁇ ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is -CH 2 -, -NH-, -O-, or -S-;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, 2, or 3;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • the heteroaryl n is non-zero if ⁇ ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • n 0 or 1
  • X 1 is NR 1 or CR 2 R 3 ⁇ wherein is a double bond, then R 1 or R 3 is nothing (null) ⁇ ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is —CH 2 —, —O—, or —S—;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, or 2;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • the heteroaryl n is non-zero if ⁇ ;
  • R is -H
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 1 may include a compound represented by Formula 2 below.
  • X 1 is NR 1 or CR 2 R 3 ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is -CH 2 -, -NH-, -O-, or -S-;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, 2, or 3;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 2 may include a compound represented by Formula 2-1 below.
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is —CH 2 —, —O—, or —S—;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, or 2;
  • L 2 is null
  • Z is -Z 1 -L 3 -Z 2 ,
  • R is -H
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 1 may include a compound represented by Formula 3 below.
  • X 1 is NR 1 or CR 2 R 3 ⁇ wherein is a double bond, then R 1 or R 3 is nothing (null) ⁇ ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is -CH 2 -, -NH-, -O-, or -S-;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, 2, or 3;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 3 may include a compound represented by Formula 3-1 below.
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is —CH 2 — or —O—
  • W 2 is —CH—
  • a to d are each independently 1 or 2;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ,
  • Z 2 is —H, heteroaryl, or null ⁇ wherein one or more H of the heteroaryl may be substituted with —C 1-4 alkyl ⁇ ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl.
  • the compound represented by Formula 1 may be selected from the group consisting of the compounds described below.
  • alkyl may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded.
  • C 1-4 alkyl can mean an alkyl containing 1 to 4 carbon atoms.
  • Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto.
  • Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, as an example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, but is limited thereto. doesn't happen
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above.
  • C 1-4 alkoxy may mean alkoxy containing C 1-4 alkyl, that is, -(OC 1-4 alkyl), for example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n - butoxy , isobutoxy , sec - butoxy ), or tert - butoxy , etc., but is not limited thereto.
  • halo may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein.
  • haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n -butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
  • hydroxyalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).
  • aminoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"), wherein R' and R" are each independently hydrogen , and may be selected from the group consisting of C 1-4 alkyl, wherein the selected R' and R" may be each independently substituted or unsubstituted.
  • cyanoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as a heterocycloalkene.
  • a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring
  • heterocycloalkyl is pyrrolidine, piperidine, imi Dazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H )- Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptan
  • arene may mean an aromatic hydrocarbon ring.
  • the arene may be a monocyclic arene or a polycyclic arene.
  • the ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. not limited In the present specification, the residue in which one hydrogen atom is removed from the "arene" is referred to as "aryl".
  • heteroene may be an aromatic ring containing at least one of O, N, P, Si, and S as a heterogeneous element.
  • the number of ring carbon atoms of heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • the polycyclic heteroarene may have, for example, a two- or three-ring structure.
  • heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, triazine, acridyl, pyridazine, pyrazine, quinoline , quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyr Limidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimid
  • enantiomer means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention.
  • a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter. or wedge-dotted join may include.
  • the compound of formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt".
  • a pharmaceutically acceptable salt As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to a concentration of a compound having an effective action relatively non-toxic and harmless to a patient, and any side effects resulting from the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid, and the organic acid may be methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used However, the present invention is not limited thereto.
  • bases can be used to prepare pharmaceutically acceptable metal salts.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p -toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.
  • the present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention since the compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against DNK-PK, it is suitable for treatment or prevention of DNA-PK-related diseases, particularly cancer. It can be useful. Since DNA-PK plays a key role in the repair process of dsDNA cleavage, inhibiting DNA-PK activity can induce cancer cell death by interfering with DNA repair in cancer cells whose cell cycle is promoted compared to normal cells. In particular, the cancer may mean a cancer having a high level of replication stress, but is not limited thereto.
  • the cancer includes all cancers capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of DNA-PK activity, and may be solid cancer or blood cancer.
  • pseudomyxoma intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, Para
  • the present invention provides a pharmaceutical composition for the treatment or prevention of cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, DNA damage It may be to further enhance the anticancer effect by being administered together in an anticancer treatment regimen that causes
  • the anti-cancer therapy may be radiation therapy or chemotherapy, but is not limited thereto.
  • the radiation therapy includes any form of treatment that can break the DNA double helix structure by causing damage to the DNA of cancer cells.
  • it may be photon irradiation (classical, electromagnetic X-ray/gamma irradiation), proton irradiation, heavy ion irradiation (ionized carbon) or neutron irradiation, but is not limited thereto.
  • the anti-tumor substance used in the chemotherapy which can be administered together with the pharmaceutical composition for the treatment or prevention of cancer of the present invention, damages the DNA of cancer cells, such as DNA replication, DNA transcription or gene expression involved in it could be
  • the anti-tumor substance may be an alkylating agent, a platinum compound, a topoisomerase inhibitor, a DNA modifier, an anticancer antibiotic, or an alpha emitter, specifically altretamine, bendamustine, busulfan, carmustine, chloroambucil, Chloromethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, threosulfan , mechloroethamine, carboquinone, apaziquin, fotemustine, gluphosp
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof provides a method for treating or preventing a DNA-PK-related disease, particularly cancer, comprising:
  • the subject may be a mammal including a human.
  • the term "therapeutically effective amount” refers to an amount of the compound represented by Formula 1 effective for treatment or prevention of a DNA-PK-related disease.
  • “therapeutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents.
  • the dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used at a dose higher than the determined dosage.
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or A use of a pharmaceutically acceptable salt thereof is provided.
  • the compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
  • Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art.
  • "including" a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
  • the pyrimidine-fused cyclic compound of the present invention exhibits excellent inhibitory activity against DNA-PK, it can be usefully used for the treatment or prevention of the DNA-PK-related disease.
  • Step 1 2-chloro-4- (tetrahydro-2H-pyran-4-yl) pyrimidine-4,5-diamine ⁇ 2-chloro-4- (tetrahydro-2H-pyran-4-yl) pyrimidine-4 Preparation of ,5-diamine ⁇
  • Step 2 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-9-(tetrahydro-2H-pyran- Preparation of 4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 3 2-Chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-7-methyl-9 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 Preparation of 2-chloro-N4-phenylpyrimidine-4,5-diamine ⁇ 2-chloro-N4-phenylpyrimidine-4,5-diamine ⁇
  • Step 2 Preparation of 2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇
  • Step 3 2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H- purin-8-one ⁇ production
  • Step 1 2-chloro-9-tetrahydro-2H-pyran-4-yl-7,9-dihydro-8H-purine-8-thione ⁇ 2-chloro-9-tetrahydro-2H-pyran-4-yl Preparation of -7,9-dihydro-8H-purine-8-thione ⁇
  • Step 2 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione ⁇ 2-chloro-7-methyl-9 -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione ⁇ production
  • Step 1 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇ 2-chloro-8-(tetrahydro-2H-pyran) Preparation of -4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Step 2 2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇ 2-chloro-5-methyl- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Preparation 18 Preparation of 2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione ⁇ 2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione ⁇
  • Step 1 Preparation of ethyl (tetrahydro-2H-pyran-4-yl)glycinate ⁇ ethyl (tetrahydro-2H-pyran-4-yl)glycinate ⁇
  • Step 2 Ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate ⁇ ethyl N-(2-chloro-5 Preparation of -nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate ⁇
  • Step 3 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 2-chloro-8-(tetrahydro-2H- Preparation of pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Step 4 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 2-chloro-5-methyl Preparation of -8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Step 1 5-bromo-2-chloro-N- (tetrahydro-2H-pyran-4-yl) pyrimidin-4-amine ⁇ 5-bromo-2-chloro-N- (tetrahydro-2H-pyran- Preparation of 4-yl)pyrimidin-4-amine ⁇
  • Step 2 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 2-chloro-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 1 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)- Preparation of 7,9-dihydro-8H-purin-8-one ⁇
  • Examples 2 to 31 were prepared in substantially the same manner as in Example 1, using appropriate intermediates and amines.
  • Example 2 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one ⁇ 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ manufacturing
  • Example 3 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one ⁇ 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ manufacture of
  • Example 4 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine -8-one ⁇ 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8- manufacture of one ⁇
  • Example 5 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H -Purin-8-one ⁇ 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro- Preparation of 8H-purin-8-one ⁇
  • Example 6 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro -8H-purin-8-one ⁇ 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Preparation of dihydro-8H-purin-8-one ⁇
  • Example 7 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one ⁇ 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)- Preparation of 7,9-dihydro-8H-purin-8-one ⁇
  • Example 8 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one ⁇ 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H) Preparation of -pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one ⁇
  • Example 9 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran Preparation of -4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 10 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-( Preparation of tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 11 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 12 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 13 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino) picolinonitrile ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Preparation of amino) picolinonitrile ⁇
  • Example 14 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Preparation of amino)picolinamide ⁇
  • Step 2 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) Preparation of picolinamide ⁇
  • a target compound was prepared in substantially the same manner as in Example 1 using 5-amino-4-methyl-picolinamide obtained in Step 1 (yield: 11%).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 1.74 (2H, d), 2.43 (3H, s), 2.76 (2H, m), 3.43 (3H, s), 3.55 (2H, t), 4.15 (3H, dd), 4.53-4.59 (1H, m), 5.52 (1H, s), 6.83-9.51 (5H, m)
  • Example 15 Methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)thi Offene-2-carboxylate ⁇ methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) Preparation of thiophene-2-carboxylate ⁇
  • Example 16 Methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)picolinate ⁇ methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2- Preparation of yl)amino)picolinate ⁇
  • Example 17 N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- yl)amino)picolinamide ⁇ N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- Preparation of 2-yl)amino)picolinamide ⁇
  • the compound of Example 17 was obtained by performing the following scheme using the compound of Example 16.
  • Example 18 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) Preparation of -7,9-dihydro-8H-purin-8-one ⁇
  • Example 19 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- Preparation of yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 20 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8 -one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ Produce
  • Example 21 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H- Purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin- Preparation of 8-one ⁇
  • Example 22 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purine-8 -one ⁇ 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ manufacture of
  • Example 23 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purine-8- Preparation of one ⁇ 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇
  • Example 24 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-thio Pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin) Preparation of -3-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 25 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7,9-di Hydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7 Preparation of ,9-dihydro-8H-purin-8-one ⁇
  • Example 26 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[3.3]heptan-2-yl) -7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro [3.3] Preparation of heptan-2-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 27 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H -Purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin- Preparation of 8-one ⁇
  • Example 28 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6 Preparation of -yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 29 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5 ] Nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl) Preparation of pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 30 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purine-8-thione ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-( Preparation of tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione ⁇
  • Example 31 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl )amino)picolinamide ⁇ 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl Preparation of )amino)picolinamide ⁇
  • Example 32 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4- Preparation of yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridin-2-amine ⁇ 4-methyl-N-(1-methyl-1H-pyrazol-4- Preparation of yl)-5-nitropyridin-2-amine ⁇
  • Step 2 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyridine-2,5-diamine ⁇ 4-methyl-N-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-2,5-diamine ⁇
  • Step 3 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H -Pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl) Preparation of )amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 33 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)pyridin-2-yl methanesulfonate ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin) Preparation of -2-yl)amino)pyridin-2-yl methanesulfonate ⁇
  • Step 1 Preparation of 4-methyl-5-nitropyridin-2-yl methanesulfonate (4-methyl-5-nitropyridin-2-yl methanesulfonate)
  • Step 2 Preparation of 5-amino-4-methylpyridin-2-yl methanesulfonate (5-amino-4-methylpyridin-2-yl methanesulfonate)
  • Step 3 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )pyridin-2-yl methanesulfonate ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- Preparation of 2-yl)amino)pyridin-2-yl methanesulfonate ⁇
  • Example 34 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 Preparation of 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇ 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇
  • Step 2 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran Preparation of -4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Examples 35 to 59 were prepared in substantially the same manner as in Example 34, using appropriate intermediates, amine derivatives and boronic acid derivatives.
  • Example 35 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 36 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 37 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 38 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 39 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 40 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 41 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 42 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 43 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 44 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino) Preparation of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 45 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 46 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 47 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin Preparation of -3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 48 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 49 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 50 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3 Preparation of -yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 51 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7 Preparation of -methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 52 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7 Preparation of -methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 53 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5 ] Nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 54 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7,9- Dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7 Preparation of ,9-dihydro-8H-purin-8-one ⁇
  • Example 55 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-morpholino-7,9 -dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9- Preparation of morpholino-7,9-dihydro-8H-purin-8-one ⁇
  • Example 56 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(spiro[2.5]octane- 6-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3) Preparation of -yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 57 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 58 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 59 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 60 2-((5-Fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H- Pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl) Preparation of )amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)aniline ⁇ 5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4) Preparation of -yl)aniline ⁇
  • Step 2 2-((5-Fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl) Preparation of amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 61 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl Preparation of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 62 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl Preparation of )-7,9-dihydro-8H-purin-8-one ⁇
  • Example 63 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl Preparation of )-7,9-dihydro-8H-purin-8-one ⁇
  • Example 64 N-(2-Methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-di Hydro-7H-purin-2-yl)amino)picolinamide ⁇ N-(2-methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4) Preparation of -yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇
  • Examples 65 to 67 were prepared in substantially the same manner as in Example 64 using appropriate amine derivatives.
  • Example 65 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) Preparation of -8,9-dihydro-7H-purin-2-yl)amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide ⁇
  • Example 66 N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-di Hydro-7H-purin-2-yl)amino)picolinamide ⁇ N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4) Preparation of -yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇
  • Example 68 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) )-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇ 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl Preparation of -8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇
  • Example 69 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)-N-(oxetan-3-yl)picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9 Preparation of -dihydro-7H-purin-2-yl)amino)-N-(oxetan-3-yl)picolinamide ⁇
  • Example 70 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Examples 71 to 101 were prepared in substantially the same manner as in Example 70, using the appropriate compounds and amine derivatives.
  • Example 71 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-thiopyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9- Preparation of (tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 72 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9 -dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl) Preparation of -7,9-dihydro-8H-purin-8-one ⁇
  • Example 73 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purine -8-one ⁇ 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8- manufacture of one ⁇
  • Example 74 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl) -7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro [3.5] Preparation of nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 75 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7 Preparation of -yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 76 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(2-oxaspiro[3.5]nonane-7 -yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9 Preparation of -(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 77 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H -Purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin- Preparation of 8-one ⁇
  • Example 78 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9-di Hydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9- Preparation of dihydro-8H-purin-8-one ⁇
  • Example 79 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purine -8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purin-8-one ⁇ manufacturing
  • Example 80 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purine-8- Preparation of one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one ⁇
  • Example 81 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[2.5]octan-6-yl) -7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro Preparation of [2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 82 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan- Preparation of 6-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 83 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4 Preparation of -yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 84 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl )-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro Preparation of -2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 85 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-((tetrahydro-2H-pyran-4- yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 86 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H -Purin-8-one ⁇ 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H Preparation of -purin-8-one ⁇
  • Example 87 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-9-((tetrahydro-2H- Pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin) Preparation of -6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 88 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-7,9 -dihydro-8H-purin-8-one ⁇ 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 7,9-dihydro-8H-purin-8-one ⁇
  • Example 89 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d Preparation of ]imidazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 90 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 91 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, 3-d]pyrimidin-7(8H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4- Preparation of yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 92 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, 3-d]pyrimidin-7(8H)-one ⁇ 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4- Preparation of yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 93 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 94 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido [2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro- Preparation of 2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 96 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 97 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one ⁇ 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 98 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2, Preparation of 4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 99 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H) -pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((7-methyl-[1,2,4]triazolo[1 Preparation of ,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 100 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2, 3-d]pyrimidin-7(8H)-one ⁇ 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl Preparation of )amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 101 (1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)- 7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate ⁇ (1R,4R)-4-(5-methyl-2-((7-methyl-[1, Preparation of 2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate ⁇
  • Example 102 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8- Dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro Preparation of -2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 103 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol- Preparation of 5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 93 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8- prepared in Example 93 in substantially the same manner as in Example 102
  • the title compound was prepared using (tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (yield: 44%).
  • Example 104 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydro pyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran Preparation of -4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 97 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-) prepared in Example 97 in substantially the same manner as in Example 102
  • the title compound was prepared using 4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (yield: 45%).
  • Example 105 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)picolinamide ⁇ 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2] Preparation of ,3-d]pyrimidin-2-yl)amino)picolinamide ⁇
  • Example 106 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)picolinamide ⁇ 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2] Preparation of ,3-d]pyrimidin-2-yl)amino)picolinamide ⁇
  • Example 107 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine -6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7- Preparation of methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 108 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine- 7(8H)-one ⁇ 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H )-one ⁇ preparation
  • Examples 109 and 110 were prepared in substantially the same manner as in Example 108, using the appropriate compounds and appropriate amine derivatives.
  • Example 109 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one ⁇ 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, Preparation of 9-dihydro-8H-purin-8-one ⁇
  • Example 110 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one ⁇ 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, Preparation of 3-d]pyrimidin-7(8H)-one ⁇
  • Example 111 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2, 3-d]pyrimidin-7(6H)-one ⁇ 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido Preparation of [2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 108 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine obtained in Example 108
  • the title compound was prepared in substantially the same manner as in Example 102 using -7(8H)-one (yield: 42%).
  • Example 112 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyri Do[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4 Preparation of -yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • the title compound was prepared in substantially the same manner as in Example 102 using pyrimidin-7(8H)-one (yield: 36%).
  • Example 113 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4 -yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl Preparation of )amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Step 1 Preparation of 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine ⁇ 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine ⁇
  • Example 34 and substantially same in a way The title compound was prepared.
  • Step 2 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl) Preparation of amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine 40 prepared in step 1 mg and 2M isopropyl magnesium chloride (in THF) 0.1 mL tetrahydrofuran 2 into mL, at room temperature for 40 minutes agitation after 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 50 mg and 2M Isopropyl Magnesium Chloride (in THF) 0.1 mL add more, at 60 °C for 16 hours stirred.
  • Example 114 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl ) pyrido [2,3-d] pyrimidin-7 (8H) -one ⁇ 5-methyl-2-((2-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino Preparation of )-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 113 and practically The title compound was prepared in the same manner using appropriate aniline derivatives and boronic acid derivatives (yield: 22%).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 1.51 (2H, d), 2.37 (6H, s), 3.07 (2H, qd), 3.49 (2H, t), 3.95 (3H, s), 4.07 (2H, dd), 5.58 (1H, tt), 6.26 (1H, s), 7.04 (1H, s), 7.37 (1H, s), 7.61 (1H, s), 7.75 (1H, s), 7.92 (1H, d), 8.61 (1H, s)
  • Example 115 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Step 1 Preparation of 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇ 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇
  • Step 2 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ 2,3-d]pyrimidin-7(8H)-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro- Preparation of 2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example Step 2 of 113 and substantially The title compound was prepared in the same manner.
  • Step 3 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example Step 2 of 102 and substantially The title compound was prepared in the same manner (yield: 11%).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 1.93 (3H, s), 2.38 (3H, s), 3.10 (2H, m), 3.48 (2H, m), 4.02 (2H, dd), 4.35 (2H, s), 5.57 (1H, m), 5.93 (1H, s), 6.34 (1H, s), 6.87 (1H, s), 7.40 (1H, s), 7.51 (1H, s), 8.02 (1H, s), 8.46 (1H, s)
  • Examples 116 and 117 were prepared in substantially the same manner as in Example 115 using appropriate intermediates, amine derivatives and boronic acid derivatives.
  • Example 116 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 117 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3- Preparation of yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 118 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8- Dihydropteridine-6,7-dione ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl) Preparation of -5,8-dihydropteridine-6,7-dione ⁇
  • Examples 119 to 148 were prepared in substantially the same manner as in Example 118, using appropriate intermediates and amine derivatives.
  • Example 119 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8- Preparation of (tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 120 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H- Preparation of pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 121 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6) Preparation of -yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 122 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 123 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 124 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6 ,7-dione ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇ manufacture of
  • Example 125 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-((tetrahydro-2H- Pyran-4-yl)methyl)-5,8-dihydropteridin-6,7-dione ⁇ 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4] Preparation of dioxin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 126 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 127 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-((tetrahydro-2H-pyran-4- yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino) Preparation of -8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 128 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-5 ,8-dihydropteridine-6,7-dione ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran- Preparation of 4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 129 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteri Din-6,7-dione ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine- Preparation of 6,7-dione ⁇
  • Example 130 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5, 8-dihydropteridine-6,7-dione ⁇ 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino Preparation of )-5,8-dihydropteridine-6,7-dione ⁇
  • Example 131 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6- yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b Preparation of ][1,4]dioxin-6-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 132 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8- Dihydropteridin-6(5H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl Preparation of )-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 133 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a Preparation of ]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 134 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8- Dihydropteridin-6(5H)-one ⁇ 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl Preparation of )-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 135 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 136 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine- 6(5H)-one ⁇ 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H) manufacture of -one ⁇
  • Example 137 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7 ,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H Preparation of -pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 138 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 139 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin- Preparation of 6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 140 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6 (5H)-one ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)- manufacture of one ⁇
  • Example 141 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-7 ,8-dihydropteridin-6(5H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran) Preparation of -4-yl)methyl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 142 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteri Din-6(5H)-one ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridin Preparation of -6(5H)-one ⁇
  • Example 143 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran-4-yl)-7, 8-dihydropteridin-6(5H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran Preparation of -4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 144 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridin-6 ,7-dione ⁇ 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ Produce
  • Examples 145 to 154 were prepared in substantially the same manner as in Example 144, using the appropriate compounds and appropriate amine derivatives.
  • Example 145 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteri din-6,7-dione ⁇ 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6, Preparation of 7-dione ⁇
  • Example 146 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7- Preparation of dione ⁇ 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ⁇
  • Example 147 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8- Dihydropteridine-6,7-dione ⁇ 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)- Preparation of 5,8-dihydropteridine-6,7-dione ⁇
  • Example 148 8-cyclohexyl-5-methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ 8-cyclohexyl-5 Preparation of -methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 149 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6 ,7-dione ⁇ 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ Produce
  • Example 150 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteri din-6,7-dione ⁇ 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6, Preparation of 7-dione ⁇
  • Example 151 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7- Preparation of dione ⁇ 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ⁇

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Abstract

The present invention relates to a pyrimidine-fused ring compound and a use thereof. The pyrimidine-fused ring compound of the present invention exhibits excellent inhibitory activity against DNA-PK and thus can be advantageously used as a therapeutic agent for DNA-PK-related diseases.

Description

DNA-PK 억제 활성을 갖는 피리미딘-융합 고리 화합물 및 이의 용도Pyrimidine-fused ring compound having DNA-PK inhibitory activity and use thereof
본 발명은 DNA-PK 억제 활성을 갖는 피리미딘-융합 고리 화합물 및 이의 용도에 관한 것이다.The present invention relates to pyrimidine-fused ring compounds having DNA-PK inhibitory activity and uses thereof.
세포 내에서 DNA는 대사활동으로 인한 요인이나 환경적 요인으로 인해 끊임없이 손상된다. 이 경우 대부분 DNA 수선 기전을 통해 정상 상태로 회복될 수 있으나, 그렇지 않은 경우 돌연변이가 발생하여 결과적으로 세포 사멸이 유발되거나 혹은 암이 발생할 수 있다. DNA 손상을 유발하는 주요 원인으로는 산화적 대사의 부산물로 형성되는 활성산소종(reactive oxygen species), 항암 치료 목적의 전리 방사선 조사(ionizing radiation), 블레오마이신과 같은 항암제 사용 등을 들 수 있다. DNA 이중 가닥 절단(double strand break; DSB)이 일어난 경우 진핵생물에서는 대표적으로 비상동 말단-연결(non-homologous end-joining; NHEJ)과 상동 재조합(homologous recombination; HR)과 같은 메커니즘을 이용하여 손상된 DNA를 수선하게 된다. In cells, DNA is constantly damaged by metabolic or environmental factors. In this case, the normal state can be restored through the DNA repair mechanism in most cases, but otherwise, mutations may occur, resulting in cell death or cancer. The main causes of DNA damage include reactive oxygen species formed as a by-product of oxidative metabolism, ionizing radiation for anticancer treatment, and use of anticancer drugs such as bleomycin. In the case of DNA double strand break (DSB), in eukaryotes, damage is typically done using mechanisms such as non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA is repaired.
NHEJ는 절단된 DNA 이중 가닥 말단을 직접 연결시키는 기전으로 세포 주기의 모든 단계에서 일어나며, 여기서 DNA-의존적 단백질 키나아제(DNA-dependent protein kinase; DNA-PK)가 핵심적인 역할을 한다. DNA-PK는 촉매 하위단위 DNA-PKcs 및 Ku 단백질의 헤테로다이머(Ku70/Ku80)로 이루어진 핵 세린/트레오닌 단백질 키나아제 복합체이다. Ku70/Ku80 헤테로다이머가 절단된 DNA 말단을 인지하고 이에 결합한 다음, DNA-PKcs가 동원되어 활성화된 복합체를 형성한다(Yoo S et al., Nucleic Acids Res 1999; 27: 4679-4686). NHEJ is a mechanism that directly connects the ends of cleaved DNA double-stranded, and occurs at all stages of the cell cycle, where DNA-dependent protein kinase (DNA-PK) plays a key role. DNA-PK is a nuclear serine/threonine protein kinase complex consisting of the catalytic subunit DNA-PKcs and a heterodimer of Ku protein (Ku70/Ku80). After the Ku70/Ku80 heterodimer recognizes and binds to the cleaved DNA end, DNA-PKcs are recruited to form an activated complex (Yoo S et al., Nucleic Acids Res 1999; 27: 4679-4686).
한편, DNA-PK 억제제는 NHEJ를 방해함으로써 DNA가 손상된 세포가 수선되지 못하고 세포 사멸하도록 유도할 수 있으므로, DNA 손상과 관련된 다양한 치료 효과를 기대할 수 있다. 예를 들어, DNA-PK 억제제인 NU7026 및 KU-0060648은 토포아이소머라제 II 억제제의 세포 독성을 증강시킬 수 있는 것으로 보고되었으며(Willmore et al., Blood 2004; 103: 4659-4665, Munck et al., Mol Cancer Ther 2012; 11: 1789-1798), NU7441은 유방암 모델에서 이온화 방사선의 효과를 강화시켰다(Ciszewski et al., Breast Cancer Res Treat 2014; 143: 47-55). 또한, DNA-PK 억제제는 ATM-결함 림프종과 같이 높은 수준의 복제 스트레스를 갖는 종양에 대해 단일 제제로서 효과적인 것으로 확인되었다(Riabinska et al., Science Translational Medicine 2013; 189: 189ra78). On the other hand, since DNA-PK inhibitors can induce cell death without repairing DNA-damaged cells by interfering with NHEJ, various therapeutic effects related to DNA damage can be expected. For example, the DNA-PK inhibitors NU7026 and KU-0060648 have been reported to be able to potentiate the cytotoxicity of topoisomerase II inhibitors (Willmore et al., Blood 2004; 103: 4659-4665, Munck et al. ., Mol Cancer Ther 2012; 11: 1789-1798), NU7441 potentiated the effect of ionizing radiation in a breast cancer model (Ciszewski et al., Breast Cancer Res Treat 2014; 143: 47-55). In addition, DNA-PK inhibitors have been shown to be effective as single agents against tumors with high levels of replication stress, such as ATM-deficient lymphoma (Riabinska et al., Science Translational Medicine 2013; 189: 189ra78).
이와 같이 DNA-PK 활성을 조절함으로써 DNA-PK 관련 질환의 치료에 유용하게 활용될 수 있는 신규 화합물에 대한 미충족된 수요가 증대되고 있다.As such, by regulating DNA-PK activity, there is an increasing unmet demand for novel compounds that can be usefully used for the treatment of DNA-PK-related diseases.
본 발명의 목적은 신규한 구조의 피리미딘-융합 고리 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.An object of the present invention is to provide a pyrimidine-fused ring compound having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 피리미딘-융합 고리 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the pyrimidine-fused ring compound.
본 발명의 다른 목적은 상기 피리미딘-융합 고리 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 피리미딘-융합 고리 화합물을 유효성분으로 포함하는 DNA-PK 관련 질환의 치료 또는 예방용 약학적 조성물, 상기 화합물을 이용한 DNA-PK 관련 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 DNA-PK 관련 질환의 치료 또는 예방 방법을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical use of the pyrimidine-fused ring compound, specifically, a pharmaceutical composition for treating or preventing a DNA-PK-related disease comprising the pyrimidine-fused ring compound as an active ingredient, To provide a method for treating or preventing a DNA-PK-related disease using the compound, or a method for treating or preventing a DNA-PK-related disease, comprising administering the compound.
상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1로 표시되는 피리미딘-융합 고리 화합물들이 DNA-PK 활성을 저해하는 것을 확인함으로써 본 발명을 완성하였다.In order to achieve the above object, as a result of research efforts of the present inventors, the present invention was completed by confirming that the pyrimidine-fused ring compounds represented by Chemical Formula 1 mentioned below inhibit DNA-PK activity.
피리미딘-융합 고리 화합물Pyrimidine-Fused Ring Compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2022002310-appb-img-000001
Figure PCTKR2022002310-appb-img-000001
상기 화학식 1에서,In Formula 1,
Figure PCTKR2022002310-appb-img-000002
는 단일결합 또는 이중결합이고;
Figure PCTKR2022002310-appb-img-000002
is a single bond or a double bond;
n은 0, 1 또는 2이고;n is 0, 1 or 2;
X1은 NR1 또는 CR2R3 이고 {여기서,
Figure PCTKR2022002310-appb-img-000003
가 이중결합인 경우 R1 또는 R3는 아무 것도 아님(null)};X 1 is NR 1 or CR 2 R 3 {wherein
Figure PCTKR2022002310-appb-img-000003
is a double bond, then R 1 or R 3 is nothing (null)};
X2는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서,
Figure PCTKR2022002310-appb-img-000004
가 단일결합인 경우 X2는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고,
Figure PCTKR2022002310-appb-img-000005
가 이중결합인 경우 X2는 -CR2- 이며, n이 0인 경우 X2는 아무 것도 아니고 X1 및 X3는 직접 연결됨};X 2 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein,
Figure PCTKR2022002310-appb-img-000004
When is a single bond, X 2 is -CR 2 R 3 -, -(C=O)- or -(C=S)-,
Figure PCTKR2022002310-appb-img-000005
when is a double bond, X 2 is -CR 2 -, and when n is 0, X 2 is nothing and X 1 and X 3 are directly linked};
X3는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서, n이 0이고
Figure PCTKR2022002310-appb-img-000006
가 단일결합인 경우, X3는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고, n이 0이고
Figure PCTKR2022002310-appb-img-000007
가 이중결합인 경우 X3는 -CR2- 임};X 3 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein n is 0 and
Figure PCTKR2022002310-appb-img-000006
When is a single bond, X 3 is -CR 2 R 3 -, -(C=O)- or -(C=S)-, n is 0 and
Figure PCTKR2022002310-appb-img-000007
is a double bond, then X 3 is -CR 2 -;
L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
Y는 -O-C1-4알킬,
Figure PCTKR2022002310-appb-img-000008
,
Figure PCTKR2022002310-appb-img-000009
, 아릴, 또는 헤테로아릴이고 {여기서, 상기
Figure PCTKR2022002310-appb-img-000010
,
Figure PCTKR2022002310-appb-img-000011
, 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};Y is -OC 1-4 alkyl,
Figure PCTKR2022002310-appb-img-000008
,
Figure PCTKR2022002310-appb-img-000009
, aryl, or heteroaryl {wherein
Figure PCTKR2022002310-appb-img-000010
,
Figure PCTKR2022002310-appb-img-000011
, aryl, or one or more H of heteroaryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo };
W1은 -CH2-, -NH-, -O-, 또는 -S-이고;W 1 is -CH 2 -, -NH-, -O-, or -S-;
W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
a 내지 d는 각각 독립적으로 0, 1, 2, 또는 3이고;a to d are each independently 0, 1, 2, or 3;
L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
Z는 -Z1-L3-Z2이고;Z is -Z 1 -L 3 -Z 2 ;
Z1은 아릴, 헤테로아릴, 또는
Figure PCTKR2022002310-appb-img-000012
이고 {여기서, 고리 A는 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
Figure PCTKR2022002310-appb-img-000013
의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있으며; 상기 헤테로아릴이
Figure PCTKR2022002310-appb-img-000014
인 경우 n은 0이 아님};Z 1 is aryl, heteroaryl, or
Figure PCTKR2022002310-appb-img-000012
and {wherein ring A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; At least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NH 2 , - NR 4 R 5 , —OH, —OR 6 , or —halo; remind
Figure PCTKR2022002310-appb-img-000013
one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-; The heteroaryl
Figure PCTKR2022002310-appb-img-000014
n is non-zero if };
L3는 -(C1-4알킬)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -(C=O)O-(C1-4알킬)-, -NH-, -O-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C 1-4 alkyl)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C =O)O-, -(C=O)O-(C 1-4 alkyl)-, -NH-, -O-, -OS(=O) 2 -, -S-, -S(=O) -, -S(=O) 2 -, or nothing (null);
Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -OH, -O-C1-4알킬, 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein said cycloalkyl, cycloalkenyl, heterocyclo one or more H of alkyl, or heterocycloalkenyl, may be substituted with -C 1-4 alkyl or -(C=O)-; at least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -OH, -OC 1- 4 may be substituted with alkyl, or -halo};
R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
R4 내지 R6는 각각 독립적으로 -C1-4알킬이다.R 4 to R 6 are each independently —C 1-4 alkyl.
또한, 본 발명의 구체예에 따르면, 상기 화학식 1에서,In addition, according to an embodiment of the present invention, in Formula 1,
Figure PCTKR2022002310-appb-img-000015
는 단일결합 또는 이중결합이고;
Figure PCTKR2022002310-appb-img-000015
is a single bond or a double bond;
n은 0 또는 1이고;n is 0 or 1;
X1은 NR1 또는 CR2R3 이고 {여기서,
Figure PCTKR2022002310-appb-img-000016
가 이중결합인 경우 R1 또는 R3는 아무 것도 아님(null)};X 1 is NR 1 or CR 2 R 3 {wherein
Figure PCTKR2022002310-appb-img-000016
is a double bond, then R 1 or R 3 is nothing (null)};
X2는 -CR2R3-, -CR2- 또는 -(C=O)- 이고 {여기서,
Figure PCTKR2022002310-appb-img-000017
가 단일결합인 경우 X2는 -CR2R3- 또는 -(C=O)- 이고,
Figure PCTKR2022002310-appb-img-000018
가 이중결합인 경우 X2는 -CR2- 이며, n이 0인 경우 X2는 아무 것도 아니고 X1 및 X3는 직접 연결됨};X 2 is -CR 2 R 3 -, -CR 2 - or -(C=O)- and {wherein,
Figure PCTKR2022002310-appb-img-000017
When is a single bond, X 2 is -CR 2 R 3 - or -(C=O)-,
Figure PCTKR2022002310-appb-img-000018
when is a double bond, X 2 is -CR 2 -, and when n is 0, X 2 is nothing and X 1 and X 3 are directly linked};
X3는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서, n이 0이고
Figure PCTKR2022002310-appb-img-000019
가 단일결합인 경우, X3는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고, n이 0이고
Figure PCTKR2022002310-appb-img-000020
가 이중결합인 경우 X3는 -CR2- 임};X 3 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein n is 0 and
Figure PCTKR2022002310-appb-img-000019
When is a single bond, X 3 is -CR 2 R 3 -, -(C=O)- or -(C=S)-, n is 0 and
Figure PCTKR2022002310-appb-img-000020
is a double bond, then X 3 is -CR 2 -;
L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
Y는 -O-C1-4알킬,
Figure PCTKR2022002310-appb-img-000021
,
Figure PCTKR2022002310-appb-img-000022
, 또는 아릴 이고 {여기서, 상기
Figure PCTKR2022002310-appb-img-000023
,
Figure PCTKR2022002310-appb-img-000024
, 또는 아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};Y is -OC 1-4 alkyl,
Figure PCTKR2022002310-appb-img-000021
,
Figure PCTKR2022002310-appb-img-000022
, or aryl and {wherein
Figure PCTKR2022002310-appb-img-000023
,
Figure PCTKR2022002310-appb-img-000024
, or one or more H of aryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo};
W1은 -CH2-, -O-, 또는 -S-이고;W 1 is —CH 2 —, —O—, or —S—;
W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
a 내지 d는 각각 독립적으로 0, 1, 또는 2이고;a to d are each independently 0, 1, or 2;
L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
Z는 -Z1-L3-Z2이고;Z is -Z 1 -L 3 -Z 2 ;
Z1은 아릴, 헤테로아릴, 또는
Figure PCTKR2022002310-appb-img-000025
이고 {여기서, 고리 A는 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
Figure PCTKR2022002310-appb-img-000026
의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있으며; 상기 헤테로아릴이
Figure PCTKR2022002310-appb-img-000027
인 경우 n은 0이 아님};Z 1 is aryl, heteroaryl, or
Figure PCTKR2022002310-appb-img-000025
and {wherein ring A is heterocycloalkyl or heterocycloalkenyl; at least one H of said aryl or heteroaryl is substituted with -C 1-4 alkyl, -C 1-4 haloalkyl, -CN, -NH 2 , -NR 4 R 5 , -OH, -OR 6 , or -halo can be; remind
Figure PCTKR2022002310-appb-img-000026
one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-; The heteroaryl
Figure PCTKR2022002310-appb-img-000027
n is non-zero if };
L3는 -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -NH-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C=O)O-, -NH-, -OS(=O) 2 - , -S-, -S(=O)-, -S(=O) 2 -, or nothing;
Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein at least one H of the heterocycloalkyl, or heterocycloalkenyl is -C may be substituted with 1-4 alkyl or -(C=O)-; one or more H of said aryl or heteroaryl may be substituted with -C 1-4 alkyl or -halo};
R은 -H이고; R is -H;
R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
R4 내지 R6는 각각 독립적으로 -C1-4알킬이다.R 4 to R 6 are each independently —C 1-4 alkyl.
또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물은 하기 화학식 2로 나타나는 화합물을 포함할 수 있다.In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may include a compound represented by Formula 2 below.
[화학식 2][Formula 2]
Figure PCTKR2022002310-appb-img-000028
Figure PCTKR2022002310-appb-img-000028
상기 화학식 2에서,In Formula 2,
X1은 NR1 또는 CR2R3 이고;X 1 is NR 1 or CR 2 R 3 ;
X3는 -(C=O)- 또는 -(C=S)- 이고;X 3 is -(C=O)- or -(C=S)-;
L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
Y는 -O-C1-4알킬,
Figure PCTKR2022002310-appb-img-000029
,
Figure PCTKR2022002310-appb-img-000030
, 아릴, 또는 헤테로아릴이고 {여기서, 상기
Figure PCTKR2022002310-appb-img-000031
,
Figure PCTKR2022002310-appb-img-000032
, 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};Y is -OC 1-4 alkyl,
Figure PCTKR2022002310-appb-img-000029
,
Figure PCTKR2022002310-appb-img-000030
, aryl, or heteroaryl {wherein
Figure PCTKR2022002310-appb-img-000031
,
Figure PCTKR2022002310-appb-img-000032
, aryl, or one or more H of heteroaryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo };
W1은 -CH2-, -NH-, -O-, 또는 -S-이고;W 1 is -CH 2 -, -NH-, -O-, or -S-;
W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
a 내지 d는 각각 독립적으로 0, 1, 2, 또는 3이고;a to d are each independently 0, 1, 2, or 3;
L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
Z는 -Z1-L3-Z2이고;Z is -Z 1 -L 3 -Z 2 ;
Z1은 아릴, 헤테로아릴, 또는
Figure PCTKR2022002310-appb-img-000033
이고 {여기서, 고리 A는 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
Figure PCTKR2022002310-appb-img-000034
의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};Z 1 is aryl, heteroaryl, or
Figure PCTKR2022002310-appb-img-000033
and {wherein ring A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; At least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NH 2 , - NR 4 R 5 , —OH, —OR 6 , or —halo; remind
Figure PCTKR2022002310-appb-img-000034
one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
L3는 -(C1-4알킬)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -(C=O)O-(C1-4알킬)-, -NH-, -O-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C 1-4 alkyl)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C =O)O-, -(C=O)O-(C 1-4 alkyl)-, -NH-, -O-, -OS(=O) 2 -, -S-, -S(=O) -, -S(=O) 2 -, or nothing (null);
Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -OH, -O-C1-4알킬, 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein said cycloalkyl, cycloalkenyl, heterocyclo one or more H of alkyl, or heterocycloalkenyl, may be substituted with -C 1-4 alkyl or -(C=O)-; at least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -OH, -OC 1- 4 may be substituted with alkyl, or -halo};
R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
R4 내지 R6는 각각 독립적으로 -C1-4알킬이다.R 4 to R 6 are each independently —C 1-4 alkyl.
상기 화학식 2로 표시되는 화합물은 하기 화학식 2-1로 나타나는 화합물을 포함할 수 있다.The compound represented by Formula 2 may include a compound represented by Formula 2-1 below.
[화학식 2-1][Formula 2-1]
Figure PCTKR2022002310-appb-img-000035
Figure PCTKR2022002310-appb-img-000035
상기 화학식 2-1에서,In Formula 2-1,
X3는 -(C=O)- 또는 -(C=S)- 이고;X 3 is -(C=O)- or -(C=S)-;
L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
Y는 -O-C1-4알킬,
Figure PCTKR2022002310-appb-img-000036
,
Figure PCTKR2022002310-appb-img-000037
, 또는 아릴이고 {여기서, 상기
Figure PCTKR2022002310-appb-img-000038
,
Figure PCTKR2022002310-appb-img-000039
, 또는 아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};Y is -OC 1-4 alkyl,
Figure PCTKR2022002310-appb-img-000036
,
Figure PCTKR2022002310-appb-img-000037
, or aryl, {wherein
Figure PCTKR2022002310-appb-img-000038
,
Figure PCTKR2022002310-appb-img-000039
, or one or more H of aryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo};
W1은 -CH2-, -O-, 또는 -S-이고;W 1 is —CH 2 —, —O—, or —S—;
W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
a 내지 d는 각각 독립적으로 0, 1, 또는 2이고;a to d are each independently 0, 1, or 2;
L2는 아무 것도 아니고(null);L 2 is null;
Z는 -Z1-L3-Z2이고, Z is -Z 1 -L 3 -Z 2 ,
Z1은 아릴, 헤테로아릴, 또는
Figure PCTKR2022002310-appb-img-000040
이고 {여기서, 고리 A는 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
Figure PCTKR2022002310-appb-img-000041
의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};Z 1 is aryl, heteroaryl, or
Figure PCTKR2022002310-appb-img-000040
and {wherein ring A is heterocycloalkyl or heterocycloalkenyl; at least one H of said aryl or heteroaryl is substituted with -C 1-4 alkyl, -C 1-4 haloalkyl, -CN, -NH 2 , -NR 4 R 5 , -OH, -OR 6 , or -halo can be; remind
Figure PCTKR2022002310-appb-img-000041
one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
L3는 -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -NH-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C=O)O-, -NH-, -OS(=O) 2 - , -S-, -S(=O)-, -S(=O) 2 -, or nothing;
Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein at least one H of the heterocycloalkyl, or heterocycloalkenyl is -C may be substituted with 1-4 alkyl or -(C=O)-; one or more H of said aryl or heteroaryl may be substituted with -C 1-4 alkyl or -halo};
R은 -H이고; R is -H;
R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
R4 내지 R6는 각각 독립적으로 -C1-4알킬이다.R 4 to R 6 are each independently —C 1-4 alkyl.
또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물은 하기 화학식 3으로 나타나는 화합물을 포함할 수 있다.In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may include a compound represented by Formula 3 below.
[화학식 3][Formula 3]
Figure PCTKR2022002310-appb-img-000042
Figure PCTKR2022002310-appb-img-000042
상기 화학식 3에서,In Formula 3,
Figure PCTKR2022002310-appb-img-000043
는 단일결합 또는 이중결합이고;
Figure PCTKR2022002310-appb-img-000043
is a single bond or a double bond;
X1은 NR1 또는 CR2R3 이고 {여기서,
Figure PCTKR2022002310-appb-img-000044
가 이중결합인 경우 R1 또는 R3는 아무 것도 아님(null)};X 1 is NR 1 or CR 2 R 3 {wherein
Figure PCTKR2022002310-appb-img-000044
is a double bond, then R 1 or R 3 is nothing (null)};
X2는 -CR2R3-, -CR2-, -(C=O)- 또는 -(C=S)- 이고 {여기서,
Figure PCTKR2022002310-appb-img-000045
가 단일결합인 경우 X2는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고,
Figure PCTKR2022002310-appb-img-000046
가 이중결합인 경우 X2는 -CR2-임};X 2 is -CR 2 R 3 -, -CR 2 -, -(C=O)- or -(C=S)-, {wherein,
Figure PCTKR2022002310-appb-img-000045
When is a single bond, X 2 is -CR 2 R 3 -, -(C=O)- or -(C=S)-,
Figure PCTKR2022002310-appb-img-000046
is a double bond, X 2 is -CR 2 -;
X3는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서, n이 0이고
Figure PCTKR2022002310-appb-img-000047
가 단일결합인 경우, X3는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고, n이 0이고
Figure PCTKR2022002310-appb-img-000048
가 이중결합인 경우 X3는 -CR2- 임};X 3 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein n is 0 and
Figure PCTKR2022002310-appb-img-000047
When is a single bond, X 3 is -CR 2 R 3 -, -(C=O)- or -(C=S)-, n is 0 and
Figure PCTKR2022002310-appb-img-000048
is a double bond, then X 3 is -CR 2 -;
L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
Y는 -O-C1-4알킬,
Figure PCTKR2022002310-appb-img-000049
,
Figure PCTKR2022002310-appb-img-000050
, 아릴, 또는 헤테로아릴이고 {여기서, 상기
Figure PCTKR2022002310-appb-img-000051
,
Figure PCTKR2022002310-appb-img-000052
, 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};Y is -OC 1-4 alkyl,
Figure PCTKR2022002310-appb-img-000049
,
Figure PCTKR2022002310-appb-img-000050
, aryl, or heteroaryl {wherein
Figure PCTKR2022002310-appb-img-000051
,
Figure PCTKR2022002310-appb-img-000052
, aryl, or one or more H of heteroaryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo };
W1은 -CH2-, -NH-, -O-, 또는 -S-이고;W 1 is -CH 2 -, -NH-, -O-, or -S-;
W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
a 내지 d는 각각 독립적으로 0, 1, 2, 또는 3이고;a to d are each independently 0, 1, 2, or 3;
L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
Z는 -Z1-L3-Z2이고; Z is -Z 1 -L 3 -Z 2 ;
Z1은 아릴, 헤테로아릴, 또는
Figure PCTKR2022002310-appb-img-000053
이고 {여기서, 고리 A는 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
Figure PCTKR2022002310-appb-img-000054
의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};Z 1 is aryl, heteroaryl, or
Figure PCTKR2022002310-appb-img-000053
and {wherein ring A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; At least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NH 2 , - NR 4 R 5 , —OH, —OR 6 , or —halo; remind
Figure PCTKR2022002310-appb-img-000054
one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
L3는 -(C1-4알킬)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -(C=O)O-(C1-4알킬)-, -NH-, -O-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C 1-4 alkyl)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C =O)O-, -(C=O)O-(C 1-4 alkyl)-, -NH-, -O-, -OS(=O) 2 -, -S-, -S(=O) -, -S(=O) 2 -, or nothing (null);
Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -OH, -O-C1-4알킬, 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein said cycloalkyl, cycloalkenyl, heterocyclo one or more H of alkyl, or heterocycloalkenyl, may be substituted with -C 1-4 alkyl or -(C=O)-; at least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -OH, -OC 1- 4 may be substituted with alkyl, or -halo};
R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
R4 내지 R6는 각각 독립적으로 -C1-4알킬이다.R 4 to R 6 are each independently —C 1-4 alkyl.
상기 화학식 3으로 표시되는 화합물은 하기 화학식 3-1로 나타나는 화합물을 포함할 수 있다.The compound represented by Formula 3 may include a compound represented by Formula 3-1 below.
[화학식 3-1][Formula 3-1]
Figure PCTKR2022002310-appb-img-000055
Figure PCTKR2022002310-appb-img-000055
상기 화학식 3-1에서,In Formula 3-1,
Figure PCTKR2022002310-appb-img-000056
는 단일결합 또는 이중결합이고 {여기서,
Figure PCTKR2022002310-appb-img-000057
가 이중결합인 경우 R3는 아무 것도 아님(null)};
Figure PCTKR2022002310-appb-img-000056
is a single bond or a double bond {where,
Figure PCTKR2022002310-appb-img-000057
R 3 is nothing when is a double bond (null)};
X2는 -CR2R3-, -CR2- 또는 -(C=O)- 이고 {여기서,
Figure PCTKR2022002310-appb-img-000058
가 단일결합인 경우 X2는 -CR2R3- 또는 -(C=O)- 이고,
Figure PCTKR2022002310-appb-img-000059
가 이중결합인 경우 X2는 -CR2- 임};X 2 is -CR 2 R 3 -, -CR 2 - or -(C=O)- and {wherein,
Figure PCTKR2022002310-appb-img-000058
When is a single bond, X 2 is -CR 2 R 3 - or -(C=O)-,
Figure PCTKR2022002310-appb-img-000059
X 2 is -CR 2 - when is a double bond;
L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
Y는
Figure PCTKR2022002310-appb-img-000060
또는
Figure PCTKR2022002310-appb-img-000061
이고 {여기서, 상기
Figure PCTKR2022002310-appb-img-000062
또는
Figure PCTKR2022002310-appb-img-000063
의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};Y is
Figure PCTKR2022002310-appb-img-000060
or
Figure PCTKR2022002310-appb-img-000061
and {wherein the
Figure PCTKR2022002310-appb-img-000062
or
Figure PCTKR2022002310-appb-img-000063
one or more H of may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo};
W1은 -CH2- 또는 -O-이고;W 1 is —CH 2 — or —O—;
W2는 -CH-이고;W 2 is —CH—;
a 내지 d는 각각 독립적으로 1 또는 2이고;a to d are each independently 1 or 2;
L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
Z는 -Z1-L3-Z2이고, Z is -Z 1 -L 3 -Z 2 ,
Z1은 아릴, 헤테로아릴, 또는
Figure PCTKR2022002310-appb-img-000064
이고 {여기서, 고리 A는 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, 또는 -할로로 치환될 수 있고; 상기
Figure PCTKR2022002310-appb-img-000065
의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};Z 1 is aryl, heteroaryl, or
Figure PCTKR2022002310-appb-img-000064
and {wherein ring A is heterocycloalkyl or heterocycloalkenyl; one or more H of said aryl or heteroaryl may be substituted with -C 1-4 alkyl, -OH, or -halo; remind
Figure PCTKR2022002310-appb-img-000065
one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
L3는 -(C=O)NH- 또는 아무 것도 아니고(null);L 3 is -(C=O)NH- or nothing (null);
Z2는 -H, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 헤테로아릴의 하나 이상의 H는 -C1-4알킬로 치환될 수 있음};Z 2 is —H, heteroaryl, or null {wherein one or more H of the heteroaryl may be substituted with —C 1-4 alkyl};
R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이다.R 1 to R 3 are each independently —H or —C 1-4 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기에 기재된 화합물로 이루어진 군으로부터 선택된 것일 수 있다.According to an embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of the compounds described below.
(1) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(1) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one;
(2) 7-메틸-2-((6-메틸퀴놀린-7-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(2) 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8 -On;
(3) 2-(벤조[d]티아졸-6-일아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(3) 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8 -On;
(4) 2-((5-히드록시나프탈렌-2-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(4) 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one;
(5) 7-메틸-2-((5-메틸-1H-인돌-6-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(5) 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one;
(6) 2-((5-클로로벤조[d]옥사졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(6) 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro- 8H-purin-8-one;
(7) 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(7) 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one;
(8) 2,2-디메틸-7-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-2H-벤조[b][1,4]옥사진-3(4H)-온;(8) 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)-2H-benzo[b][1,4]oxazin-3(4H)-one;
(9) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(9) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
(10) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(10) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purin-8-one;
(11) 2-((4,7-디메틸-2-옥소-2H-크로멘-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(11) 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
(12) 7-메틸-2-((4-메틸-6-(4-메틸-1H-이미다졸-1-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(12) 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
(13) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리노니트릴;(13) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) picolinonitrile;
(14) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(14) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )picolinamide;
(15) 메틸 5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)티오펜-2-카르복실레이트;(15) methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)thiophene -2-carboxylate;
(16) 메틸 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리네이트;(16) methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) amino) picolinate;
(17) N,4-디메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(17) N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)picolinamide;
(18) 7-메틸-2-((4-메틸-6-(메틸티오)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(18) 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one;
(19) 7-메틸-2-((4-메틸-6-(트리플루오로메틸)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(19) 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one;
(20) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온;(20) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purine-8- On;
(21) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온;(21) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purine -8-one;
(22) 2-((4,7-디메틸-2-옥소-2H-크로멘-6-일)아미노)-7-메틸-9-페닐-7,9-디하이드로-8H-푸린-8-온;(22) 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purine-8- On;
(23) 7-메틸-2-((4-메틸-6-(트리플루오로메틸)피리딘-3-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온;(23) 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one ;
(24) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(24) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-thiopyran -4-yl)-7,9-dihydro-8H-purin-8-one;
(25) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(스피로[3.3]헵탄-2-일)-7,9-디하이드로-8H-푸린-8-온;(25) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7,9-dihydro -8H-purin-8-one;
(26) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(스피로[3.3]헵탄-2-일)-7,9-디하이드로-8H-푸린-8-온;(26) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[3.3]heptan-2-yl)- 7,9-dihydro-8H-purin-8-one;
(27) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-9-(3-메톡시사이클로부틸)-7-메틸-7,9-디하이드로-8H-푸린-8-온;(27) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H- purin-8-one;
(28) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-옥사스피로[3.3]헵탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(28) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9 -dihydro-8H-purin-8-one;
(29) 7-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(29) 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5] nonan-7-yl)-7,9-dihydro-8H-purin-8-one;
(30) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온;(30) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purine-8-thione;
(31) 4-메틸-5-((7-메틸-9-(테트라하이드로-2H-피란-4-일)-8-티옥소-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(31) 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl) amino)picolinamide;
(32) 7-메틸-2-((4-메틸-6-((1-메틸-1H-피라졸-4-일)아미노)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(32) 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
(33) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피리딘-2-일 메탄설포네이트;(33) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) pyridin-2-yl methanesulfonate;
(34) 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(34) 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
(35) 7-메틸-2-((4-메틸-6-(3-메틸티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(35) 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
(36) 7-메틸-2-((4-메틸-6-(5-메틸티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(36) 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
(37) 7-메틸-2-((4-메틸-6-(티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(37) 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
(38) 2-((6-(푸란-3-일)-2-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(38) 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
(39) 7-메틸-2-((4-메틸-6-(티오펜-3-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(39) 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
(40) 7-메틸-2-((4-메틸-6-(5-메틸푸란-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(40) 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purin-8-one;
(41) 2-((6-(푸란-2-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(41) 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
(42) 7-메틸-2-((4-메틸-6-(2-메틸옥사졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(42) 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
(43) 7-메틸-2-((4-메틸-6-(2-메틸티아졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(43) 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
(44) 7-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(44) 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one;
(45) 7-메틸-2-((4-메틸-6-(옥사졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(45) 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
(46) 7-메틸-2-((4-메틸-6-(옥사졸-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(46) 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
(47) 2-((6-(벤조[d][1,3]디옥솔-5-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(47) 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
(48) 7-메틸-2-((4-메틸-6-(5-메틸이소옥사졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(48) 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
(49) 7-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(49) 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
(50) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피롤-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(50) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one;
(51) 2-((6-(2,5-디하이드로푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(51) 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one;
(52) 2-((6-(4,5-디하이드로푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(52) 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one;
(53) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(53) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5] nonan-7-yl)-7,9-dihydro-8H-purin-8-one;
(54) 7-메틸-2-((4-메틸-6-(티오펜-2-일)피리딘-3-일)아미노)-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온;(54) 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7,9-di hydro-8H-purin-8-one;
(55) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온;(55) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-morpholino-7,9- dihydro-8H-purin-8-one;
(56) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(56) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(spiro[2.5]octane-6 -yl)-7,9-dihydro-8H-purin-8-one;
(57) 7-에틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(57) 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
(58) 7-에틸-2-((4-메틸-6-(옥사졸-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(58) 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
(59) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(59) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
(60) 2-((5-플루오로-2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(60) 2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one;
(61) 2-((5-플루오로-2-메틸-4-(2-메틸옥사졸-5-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(61) 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one;
(62) 7-메틸-2-((4-메틸-6-(메틸술포닐)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(62) 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- dihydro-8H-purin-8-one;
(63) 7-메틸-2-((4-메틸-6-(메틸술피닐)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(63) 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- dihydro-8H-purin-8-one;
(64) N-(2-메톡시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(64) N-(2-methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro -7H-purin-2-yl)amino)picolinamide;
(65) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-N-((테트라하이드로푸란-2-일)메틸)피콜린아미드;(65) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )-N-((tetrahydrofuran-2-yl)methyl)picolinamide;
(66) N-(2-히드록시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(66) N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro -7H-purin-2-yl)amino)picolinamide;
(67) N-(2,2-디메톡시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(67) N-(2,2-dimethoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9- dihydro-7H-purin-2-yl)amino)picolinamide;
(68) 4-메틸-N-(1-메틸-1H-피라졸-4-일)-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(68) 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) -8,9-dihydro-7H-purin-2-yl)amino)picolinamide;
(69) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-N-(옥세탄-3-일)피콜린아미드;(69) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )-N-(oxetan-3-yl)picolinamide;
(70) 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(70) 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
(71) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(71) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl )-7,9-dihydro-8H-purin-8-one;
(72) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(72) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9- dihydro-8H-purin-8-one;
(73) 7-메틸-2-((7-메틸퀴놀린-6-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(73) 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purine- 8-one;
(74) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(74) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)- 7,9-dihydro-8H-purin-8-one;
(75) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(75) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9 -dihydro-8H-purin-8-one;
(76) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(76) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(2-oxaspiro[3.5]nonane-7- yl)-7,9-dihydro-8H-purin-8-one;
(77) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온;(77) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H- purin-8-one;
(78) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온;(78) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9-dihydro -8H-purin-8-one;
(79) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온;(79) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purine- 8-one;
(80) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온;(80) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one ;
(81) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(81) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)- 7,9-dihydro-8H-purin-8-one;
(82) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(82) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9 -dihydro-8H-purin-8-one;
(83) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(83) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7, 9-dihydro-8H-purin-8-one;
(84) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(84) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl) -7,9-dihydro-8H-purin-8-one;
(85) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(85) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl) )methyl)-7,9-dihydro-8H-purin-8-one;
(86) 7-메틸-2-((7-메틸퀴놀린-6-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(86) 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H- purin-8-one;
(87) 7-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(87) 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-9-((tetrahydro-2H-pyran) -4-yl)methyl)-7,9-dihydro-8H-purin-8-one;
(88) 9-(2-메톡시에틸)-7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-7,9-디하이드로-8H-푸린-8-온;(88) 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-7,9- dihydro-8H-purin-8-one;
(89) 7-메틸-2-((6-메틸-2-옥소-2,3-디하이드로-1H-벤조[d]이미다졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(89) 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-9-(tetrahydro-2H- pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
(90) 6-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(90) 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
(91) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(91) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;
(92) 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(92) 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;
(93) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(93) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) pyrido[2,3-d]pyrimidin-7(8H)-one;
(94) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(94) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[ 2,3-d]pyrimidin-7(8H)-one;
(95) 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온; (95) 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one;
(96) 5-에틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(96) 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
(97) 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(97) 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one;
(98) 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온;(98) 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) )amino)pyrido[2,3-d]pyrimidin-7(8H)-one;
(99) 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)피리도[2,3-d]피리미딘-7(8H)-온;(99) 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H- pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one;
(100) 8-사이클로헥실-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온;(100) 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3 -d]pyrimidin-7(8H)-one;
(101) (1R,4R)-4-(5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)-7-옥소피리도[2,3-d]피리미딘-8(7H)-일)사이클로헥실아세테이트;(101) (1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7 -oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate;
(102) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온; (102) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-di hydropyrido[2,3-d]pyrimidin-7(6H)-one;
(103) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(103) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
(104) 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온; (104) 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyri do[2,3-d]pyrimidin-7(6H)-one;
(105) 4-메틸-5-((5-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜린아미드;(105) 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrido midin-2-yl)amino)picolinamide;
(106) 4-메틸-5-((6-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜린아미드;(106) 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrido midin-2-yl)amino)picolinamide;
(107) 8-((1R,4R)-4-히드록시사이클로헥실)-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온;(107) 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one;
(108) 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(108) 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine-7 (8H)-one;
(109) 2-((2-(6-메톡시피리딘-3-일)에틸)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(109) 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro -8H-purin-8-one;
(110) 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(110) 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d] pyrimidin-7(8H)-one;
(111) 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(111) 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3 -d]pyrimidin-7(6H)-one;
(112) 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(112) 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido [2,3-d]pyrimidin-7(6H)-one;
(113) 5-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온; (113) 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
(114) 5-메틸-2-((2-메틸-4-(1-메틸-1H-피라졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(114) 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl) pyrido[2,3-d]pyrimidin-7(8H)-one;
(115) 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(115) 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
(116) 2-((6-(푸란-2-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(116) 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
(117) 5-에틸-2-((4-메틸-6-(티오펜-3-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(117) 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
(118) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(118) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-di hydropteridine-6,7-dione;
(119) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(119) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione;
(120) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(120) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropteridine-6,7-dione;
(121) 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(121) 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran- 4-yl)-5,8-dihydropteridine-6,7-dione;
(122) 5-메틸-2-((2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(122) 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione;
(123) 5-메틸-2-((2-메틸-4-(1-메틸-1H-피라졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(123) 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione;
(124) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(124) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6, 7-dione;
(125) 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(125) 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-((tetrahydro-2H-pyran) -4-yl)methyl)-5,8-dihydropteridin-6,7-dione;
(126) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(126) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl) -5,8-dihydropteridine-6,7-dione;
(127) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(127) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl) )methyl)-5,8-dihydropteridine-6,7-dione;
(128) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(128) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-5, 8-dihydropteridine-6,7-dione;
(129) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(129) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine -6,7-dione;
(130) 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(130) 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8 -dihydropteridine-6,7-dione;
(131) 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(131) 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) )amino)-5,8-dihydropteridine-6,7-dione;
(132) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(132) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-di hydropteridin-6(5H)-one;
(133) 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(133) 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one;
(134) 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(134) 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-di hydropteridin-6(5H)-one;
(135) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(135) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) -7,8-dihydropteridin-6(5H)-one;
(136) 2-((5-히드록시나프탈렌-2-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(136) 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6 (5H)-one;
(137) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(137) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7, 8-dihydropteridin-6(5H)-one;
(138) 5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(138) 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran- 4-yl)-7,8-dihydropteridin-6(5H)-one;
(139) 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(139) 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran- 4-yl)-7,8-dihydropteridin-6(5H)-one;
(140) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(140) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6( 5H)-on;
(141) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-((테트라하이드로-2H-피란-4-일)메틸)-7,8-디하이드로프테리딘-6(5H)-온;(141) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-7, 8-dihydropteridin-6(5H)-one;
(142) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-7,8-디하이드로프테리딘-6(5H)-온;(142) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridine -6(5H)-one;
(143) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5,7-디메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(143) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran-4-yl)-7,8 -dihydropteridin-6(5H)-one;
(144) 8-사이클로헥실-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(144) 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6, 7-dione;
(145) 8-사이클로헥실-5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(145) 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine -6,7-dione;
(146) 8-사이클로헥실-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온;(146) 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ;
(147) 8-사이클로헥실-5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(147) 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8-di hydropteridine-6,7-dione;
(148) 8-사이클로헥실-5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(148) 8-cyclohexyl-5-methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione;
(149) 8-사이클로펜틸-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(149) 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6, 7-dione;
(150) 8-사이클로펜틸-5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(150) 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine -6,7-dione;
(151) 8-사이클로펜틸-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온;(151) 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7-dione ;
(152) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(2-옥사스피로[3.5]노난-7-일)-5,8-디하이드로프테리딘-6,7-디온;(152) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(2-oxaspiro[3.5]nonane-7- yl)-5,8-dihydropteridine-6,7-dione;
(153) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(2-옥사스피로[3.5]노난-7-일)-5,8-디하이드로프테리딘-6,7-디온;(153) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(2-oxaspiro[3.5]nonan-7-yl)- 5,8-dihydropteridine-6,7-dione;
(154) 8-사이클로부틸-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온;(154) 8-cyclobutyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ;
(155) 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온; 및(155) 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-5,8-di hydropteridine-6,7-dione; and
(156) 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온.(156) 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-5,8-di hydropteridine-6,7-dione.
본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-4알킬"은 탄소 원자를 1 내지 4 개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2 급 (sec)-부틸, 아이소부틸, 또는 3 급 (tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. In the present invention, unless otherwise specified, "alkyl" may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded. For example, "C 1-4 alkyl" can mean an alkyl containing 1 to 4 carbon atoms. Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, as an example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, but is limited thereto. doesn't happen
본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-4의 알콕시"는 C1-4의 알킬을 함유하는 알콕시, 즉, -(O-C1-4알킬)을 의미할 수 있으며, 일 예로서, 알콕시는 메톡시 (methoxy), 에톡시 (ethoxy), n-프로폭시 (n-propoxy), 아이소프로폭시 (isopropoxy), n-부톡시 (n-butoxy), 아이소부톡시 (isobutoxy), sec-부톡시 (sec-butoxy), 또는 tert-부톡시 (tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C 1-4 alkoxy" may mean alkoxy containing C 1-4 alkyl, that is, -(OC 1-4 alkyl), for example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n - butoxy , isobutoxy , sec - butoxy ), or tert - butoxy , etc., but is not limited thereto.
본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, "halo" may be F, Cl, Br, or I.
본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬 (탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n -butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
본 발명에 있어서, "하이드록시알킬"은 하이드록시(OH)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬 (탄화수소)을 의미할 수 있다.In the present invention, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).
본 발명에 있어서, "아미노알킬"은 아미노 (NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬 (탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, 및 C1-4알킬로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R' 및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다.In the present invention, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"), wherein R' and R" are each independently hydrogen , and may be selected from the group consisting of C 1-4 alkyl, wherein the selected R' and R" may be each independently substituted or unsubstituted.
본 발명에 있어서, "시아노알킬"은 시아노 (CN)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬 (탄화수소)을 의미할 수 있다. In the present invention, "cyanoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).
본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12원 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring. In addition, "3 to 12 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, for example, heterocycloalkyl is pyrrolidine, piperidine, imi Dazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H )- Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, ( 1R , 5S )-3-azabicyclo[3.2.1] octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or (1 R ,4 R )-2-oxa-5-azabicyclo[2.2.2]octane, etc. However, the present invention is not limited thereto.
본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. not limited In the present specification, the residue in which one hydrogen atom is removed from the "arene" is referred to as "aryl".
본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 방향족 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로아렌은 단환식 헤테로아렌 또는 다환식 헤테로아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 트라이아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진, 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤, 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, "heteroarene" may be an aromatic ring containing at least one of O, N, P, Si, and S as a heterogeneous element. The number of ring carbon atoms of heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two- or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, triazine, acridyl, pyridazine, pyrazine, quinoline , quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyr Limidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole , benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosyl roll, dibenzofuran, and the like, but is not limited thereto. In the present specification, the residue in which one hydrogen atom is removed from the "heteroarene" is referred to as "heteroaryl".
본 발명에 있어서, 용어 "광학 이성질체(enantiomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 각각의 광학 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합 (-)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합
Figure PCTKR2022002310-appb-img-000066
또는 쐐기형 점선 결합
Figure PCTKR2022002310-appb-img-000067
을 포함할 수 있다.In the present invention, the term "enantiomer" means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise noted, a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter.
Figure PCTKR2022002310-appb-img-000066
or wedge-dotted join
Figure PCTKR2022002310-appb-img-000067
may include.
본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound of formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to a concentration of a compound having an effective action relatively non-toxic and harmless to a patient, and any side effects resulting from the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.In this case, an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid, and the organic acid may be methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used However, the present invention is not limited thereto.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, bases can be used to prepare pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p -toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.
피리미딘-융합 고리 화합물의 용도Uses of pyrimidine-fused ring compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다.The present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2022002310-appb-img-000068
Figure PCTKR2022002310-appb-img-000068
상기 화학식 1은 위에서 정의한 바와 같다.Formula 1 is as defined above.
본 발명의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 DNK-PK에 대하여 억제 활성을 나타내므로, DNA-PK 관련 질환, 특히, 암에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. DNA-PK는 dsDNA 절단의 수선 과정에서 핵심적인 역할을 담당하므로, DNA-PK 활성을 억제함으로써 정상 세포에 비해 세포 주기가 촉진된 암 세포에서 DNA 수선을 방해하여 암 세포 사멸을 유도할 수 있다. 특히, 상기 암은 높은 수준의 복제 스트레스를 갖는 암을 의미하는 것일 수 있으나, 이에 제한되는 것은 아니다.Since the compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against DNK-PK, it is suitable for treatment or prevention of DNA-PK-related diseases, particularly cancer. It can be useful. Since DNA-PK plays a key role in the repair process of dsDNA cleavage, inhibiting DNA-PK activity can induce cancer cell death by interfering with DNA repair in cancer cells whose cell cycle is promoted compared to normal cells. In particular, the cancer may mean a cancer having a high level of replication stress, but is not limited thereto.
본 발명에 있어서, 상기 암은 DNA-PK 활성 억제로 인해 치료 또는 예방 효능을 나타낼 수 있는 모든　암을 포함하며, 고형암　또는 혈액암일 수 있다. 예컨대, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되지 않는다. 또한, 상기 암은 원발성 암뿐 아니라 전이성 암도 포함한다.In the present invention, the cancer includes all cancers capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of DNA-PK activity, and may be solid cancer or blood cancer. For example, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer , breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, Pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus cancer It may be at least one selected from the group consisting of, but is not limited thereto. In addition, the cancer includes not only primary cancer but also metastatic cancer.
본 발명의 일 구체예에 따르면, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 치료 또는 예방용 약학적 조성물은 DNA 손상을 유발하는 항암 치료 요법에서 함께 투여됨으로써 항암 효과를 더욱 증진시키는 것일 수 있다. 상기 항암 치료 요법은 방사선 요법 또는 화학 요법일 수 있으나 이에 제한되지 않는다. According to one embodiment of the present invention, the present invention provides a pharmaceutical composition for the treatment or prevention of cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, DNA damage It may be to further enhance the anticancer effect by being administered together in an anticancer treatment regimen that causes The anti-cancer therapy may be radiation therapy or chemotherapy, but is not limited thereto.
상기 방사선 요법은 암 세포의 DNA에 손상을 유발하여 DNA 이중 나선 구조를 절단시킬 수 있는 모든 형태의 치료 요법을 포함한다. 예컨대, 광자 조사(고전적, 전자기 X-선/감마 조사), 양성자 조사, 중이온 조사(이온화 탄소) 또는 중성자 조사일 수 있으나, 이에 제한되는 것은 아니다. The radiation therapy includes any form of treatment that can break the DNA double helix structure by causing damage to the DNA of cancer cells. For example, it may be photon irradiation (classical, electromagnetic X-ray/gamma irradiation), proton irradiation, heavy ion irradiation (ionized carbon) or neutron irradiation, but is not limited thereto.
본 발명의 암의 치료 또는 예방용 약학적 조성물과 함께 투여될 수 있는 상기 화학 요법에 사용되는 항종양 물질은 암 세포의 DNA에 손상을 주는 것으로, 예컨대 DNA 복제, DNA 전사 또는 유전자 발현에 관여하는 것일 수 있다. 상기 항종양 물질은 알킬화제, 백금 화합물, 토포아이소머라제 저해제, DNA 변형제, 항암 항생제 또는 알파 방사체일 수 있고, 구체적으로 알트레타민, 벤다무스틴, 부술판, 카르무스틴, 클로로암부실, 클로로메틴, 시클로포스파미드, 다카르바진, 이포스파미드, 임프로술판 토실레이트, 로무스틴, 멜팔란, 미토브로니톨, 미토락톨, 니무스틴, 라니무스틴, 테모졸로미드, 티오테파, 트레오술판, 메클로로에타민, 카르보퀴온, 아파지퀀, 포테무스틴, 글루포스파미드, 팔리포스파미드, 피포브로만, 트로포스파미드, 우라무스틴, 카르보플라틴, 시스플라틴, 에프타플라틴, 미리플라틴 히드레이트, 옥살리플라틴, 로바플라틴, 네다플라틴, 사트라플라틴, 에토포시드, 이리노테칸, 라족산, 소부족산, 암루비신, 비산트렌, 데시타빈, 미톡산트론, 프로카르바진, 트라벡테딘, 클로파라빈, 암사크린, 브로스탈리신, 픽산트론, 라로무스틴, 블레오마이신, 닥티노마이신, 독소루비신, 에피루비신, 이다루비신, 레바미솔, 밀테포신, 미토마이신 C, 로미데프신, 스트렙토조신, 발루비신, 지노스타틴, 조루비신, 다우누로비신, 플리카마이신, 아클라루비신, 페플로마이신, 피라루비신, 알파라딘(223Ra 디클로라이드, Xofgio), 211At, 213Bi, 225Ac 또는 227Th일 수 있으나, 이에 제한되지 않는다. The anti-tumor substance used in the chemotherapy, which can be administered together with the pharmaceutical composition for the treatment or prevention of cancer of the present invention, damages the DNA of cancer cells, such as DNA replication, DNA transcription or gene expression involved in it could be The anti-tumor substance may be an alkylating agent, a platinum compound, a topoisomerase inhibitor, a DNA modifier, an anticancer antibiotic, or an alpha emitter, specifically altretamine, bendamustine, busulfan, carmustine, chloroambucil, Chloromethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, threosulfan , mechloroethamine, carboquinone, apaziquin, fotemustine, gluphosphamide, palfosfamide, pipobroman, trophosphamide, uramustine, carboplatin, cisplatin, eftaplatin, Miri Platin hydrate, oxaliplatin, lovaplatin, nedaplatin, satraplatin, etoposide, irinotecan, lasoxane, sobunic acid, amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, Trabectedin, clofarabine, amsacrine, brostalysin, pixantrone, laromustine, bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosin, mitomycin C, lomy Defcin, streptozocin, valrubicin, ginostatin, zorubicin, daunurobicin, plicamycin, aclarubicin, peplomycin, pyrarubicin, alfaradin ( 223 Ra dichloride, Xofgio), 211 At, 213 Bi, 225 Ac, or 227 Th, but is not limited thereto.
본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다. The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, DNA-PK 관련 질환, 특히 암을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 포유류일 수 있다.Also, according to one embodiment of the present invention, the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof It provides a method for treating or preventing a DNA-PK-related disease, particularly cancer, comprising: The subject may be a mammal including a human.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 DNA-PK 관련 질환의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.As used herein, the term "therapeutically effective amount" refers to an amount of the compound represented by Formula 1 effective for treatment or prevention of a DNA-PK-related disease. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used at a dose higher than the determined dosage.
또한 본 발명의 일 구체예에 따르면, 본 발명은 DNA-PK 관련 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.Also, according to one embodiment of the present invention, the present invention provides a compound represented by Formula 1, an optical isomer thereof, or A use of a pharmaceutically acceptable salt thereof is provided. The compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the uses, compositions, and methods of treatment of the present invention are equally applicable as long as they do not contradict each other.
본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, "including" a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
본 발명의 피리미딘-융합 고리 화합물은 DNA-PK에 대해 우수한 억제 활성을 나타내므로, 상기 DNA-PK 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있다.Since the pyrimidine-fused cyclic compound of the present invention exhibits excellent inhibitory activity against DNA-PK, it can be usefully used for the treatment or prevention of the DNA-PK-related disease.
이하, 본 발명을 제조예, 실시예 및 실험예에 의하여 상세히 설명한다. 단, 하기 제조예, 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Preparation Examples, Examples and Experimental Examples. However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.
제조예 1: 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Preparation Example 1: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
단계 1: 2-클로로-4-(테트라하이드로-2H-피란-4-일)피리미딘-4,5-디아민 {2-chloro-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine}의 제조Step 1: 2-chloro-4- (tetrahydro-2H-pyran-4-yl) pyrimidine-4,5-diamine {2-chloro-4- (tetrahydro-2H-pyran-4-yl) pyrimidine-4 Preparation of ,5-diamine}
Figure PCTKR2022002310-appb-img-000069
Figure PCTKR2022002310-appb-img-000069
2,4-디클로로피리미딘-5-아민 1.00 g, 테트라하이드로-2H-피란-4-아민 0.62 g, 디이소프로필에틸아민 1.58 g을 n-부탄올 10 mL에 넣고, 4 시간 동안 환류 교반하였다. 상온으로 냉각한 후 감압 농축하여 용매를 제거하고 Prep-HPLC로 정제하여 표제 화합물을 수득하였다(수득률: 70 %). 1H-NMR (400MHz, CD3OD) δ 1.53-1.65 (2H, m), 1.97-2.02 (2H, m), 3.53-3.59 (2H, m), 3.94 (2H, m), 4.18-4.25 (1H, m), 7.42 (1H, s)1.00 g of 2,4-dichloropyrimidin-5-amine, 0.62 g of tetrahydro-2H-pyran-4-amine, and 1.58 g of diisopropylethylamine were placed in 10 mL of n-butanol, and the mixture was stirred under reflux for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove the solvent and purified by Prep-HPLC to obtain the title compound (yield: 70%). 1 H-NMR (400 MHz, CD 3 OD) δ 1.53-1.65 (2H, m), 1.97-2.02 (2H, m), 3.53-3.59 (2H, m), 3.94 (2H, m), 4.18-4.25 ( 1H, m), 7.42 (1H, s)
단계 2: 2-클로로-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Step 2: 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one {2-chloro-9-(tetrahydro-2H-pyran- Preparation of 4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000070
Figure PCTKR2022002310-appb-img-000070
단계 1에서 제조된 2-클로로-4-(테트라하이드로-2H-피란-4-일)피리미딘-4,5-디아민 0.98 g 및 카보디이미다졸 1.12 g을 아세토니트릴 10 mL에 넣고 3 시간 동안 환류 교반하였다. 상온으로 냉각한 후 생성된 고체를 여과하고 실온에서 감압 건조하여 표제 화합물을 수득하였다(수득률: 70 %). 1H-NMR (400MHz, CDCl3) δ 1.75 (2H, dd), 2.71-2.81 (2H, m), 3.54 (3H, s), 4.14 (2H, dd), 4.56-4.64 (1H, m), 8.15 (1H, s)0.98 g of 2-chloro-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine and 1.12 g of carbodiimidazole prepared in step 1 were put in 10 mL of acetonitrile and for 3 hours It was stirred at reflux. After cooling to room temperature, the resulting solid was filtered and dried under reduced pressure at room temperature to obtain the title compound (yield: 70%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.75 (2H, dd), 2.71-2.81 (2H, m), 3.54 (3H, s), 4.14 (2H, dd), 4.56-4.64 (1H, m), 8.15 (1H, s)
단계 3: 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Step 3: 2-Chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000071
Figure PCTKR2022002310-appb-img-000071
단계 2에서 제조된 2-클로로-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 0.77 g을 디메틸포름아미드 3 mL에 넣고 0 ℃로 냉각하였다. 60 % 소듐하이드라이드 0.24 g, 아이오도메탄 1.28 g을 순차적으로 투입하고 0 ℃에서 1 시간 동안 교반하였다. 상온에서 2 시간 동안 교반한 후 정제수 20 mL을 넣었다. 생성된 고체를 여과하고 실온에서 감압 건조하여 표제 화합물을 수득하였다(수득률: 60 %). 1H-NMR (400MHz, CDCl3) δ 1.71 (2H, dd), 2.68-2.79 (2H, m), 3.45 (3H, s), 3.50-3.57 (2H, m), 4.13 (2H, dd), 4.55-4.63 (1H, m), 8.02 (1H, s).0.77 g of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one prepared in step 2 was placed in 3 mL of dimethylformamide and 0 °C was cooled with 0.24 g of 60% sodium hydride and 1.28 g of iodomethane were sequentially added and stirred at 0° C. for 1 hour. After stirring at room temperature for 2 hours, 20 mL of purified water was added. The resulting solid was filtered and dried under reduced pressure at room temperature to obtain the title compound (yield: 60%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.71 (2H, dd), 2.68-2.79 (2H, m), 3.45 (3H, s), 3.50-3.57 (2H, m), 4.13 (2H, dd), 4.55-4.63 (1H, m), 8.02 (1H, s).
제조예 2: 2-클로로-7-메틸-9-페닐-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one}의 제조Preparation 2: 2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H Preparation of -purin-8-one}
단계 1: 2-클로로-N4-페닐피리미딘-4,5-디아민 {2-chloro-N4-phenylpyrimidine-4,5-diamine}의 제조Step 1: Preparation of 2-chloro-N4-phenylpyrimidine-4,5-diamine {2-chloro-N4-phenylpyrimidine-4,5-diamine}
Figure PCTKR2022002310-appb-img-000072
Figure PCTKR2022002310-appb-img-000072
2,4-디클로로피리미딘-5-아민 1.00 g, 아닐린 0.57 g, 디이소프로필에틸아민 1.58 g을 반응기에 넣고 n-부탄올 10 mL을 주입하였다. 4 시간 동안 환류 교반한 후 상온으로 냉각하였다. 감압 농축하여 용매를 제거하고 MPLC로 정제하여 표제 화합물을 수득하였다. NMR 확인없이 다음 단계를 수행하였다(수득률: 78 %).1.00 g of 2,4-dichloropyrimidin-5-amine, 0.57 g of aniline, and 1.58 g of diisopropylethylamine were placed in a reactor, and 10 mL of n-butanol was injected. After stirring under reflux for 4 hours, it was cooled to room temperature. The solvent was removed by concentration under reduced pressure and purified by MPLC to obtain the title compound. The next step was performed without NMR confirmation (yield: 78%).
단계 2: 2-클로로-9-페닐-7,9-디하이드로-8H-푸린-8-온 {2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one}의 제조Step 2: Preparation of 2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one {2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000073
Figure PCTKR2022002310-appb-img-000073
단계 1에서 제조된 2-클로로-N4-페닐피리미딘-4,5-디아민 1.00 g, 카보디이미다졸 1.47 g을 반응기에 넣고 아세토니트릴 10 mL을 주입하였다. 3 시간 동안 환류 교반한 후 에틸아세테이트와 포화 암모늄클로라이드 수용액을 주입하였다. 에틸아세테이트 층을 분리하여 감압 농축하고, MPLC로 정제하여 표제 화합물을 수득하였다(수득률: 70 %). 1H-NMR (400MHz, DMSO-d6) δ 7.40-7.55 (1H, m), 7.55-7.65 (4H, m), 8.24 (1H, s)1.00 g of 2-chloro-N4-phenylpyrimidine-4,5-diamine prepared in step 1 and 1.47 g of carbodiimidazole were placed in a reactor, and 10 mL of acetonitrile was injected. After stirring under reflux for 3 hours, ethyl acetate and saturated aqueous ammonium chloride solution were injected. The ethyl acetate layer was separated, concentrated under reduced pressure, and purified by MPLC to obtain the title compound (yield: 70%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.40-7.55 (1H, m), 7.55-7.65 (4H, m), 8.24 (1H, s)
단계 3: 2-클로로-7-메틸-9-페닐-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one} 제조Step 3: 2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H- purin-8-one} production
Figure PCTKR2022002310-appb-img-000074
Figure PCTKR2022002310-appb-img-000074
단계 2에서 제조된 2-클로로-9-페닐-7,9-디하이드로-8H-푸린-8-온 1.06 g (4.3 mmol)을 반응기에 넣고 디메틸포름아미드 3 mL을 주입하였다. 0 ℃로 냉각한 후, 60 % 소듐하이드라이드 0.22 g 및 아이오도메탄 0.73 g을 순차적으로 투입하였다. 1 시간 동안 냉각 교반 후 상온에서 2 시간 동안 교반하였다. 정제수 20 mL을 주입하여 고체를 생성시킨 후 여과하였다. 실온에서 건조하여 표제 화합물을 수득하였다(수득률: 62 %). 1H-NMR (400MHz, CDCl3) δ 3.52 (3H, s), 7.40-7.46 (1H, m), 7.50-7.58 (2H, m), 7.60-7.66 (2H, m), 8.12 (1H, s)1.06 g (4.3 mmol) of 2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one prepared in step 2 was put into a reactor, and 3 mL of dimethylformamide was injected. After cooling to 0 °C, 0.22 g of 60% sodium hydride and 0.73 g of iodomethane were sequentially added. After cooling stirring for 1 hour, the mixture was stirred at room temperature for 2 hours. 20 mL of purified water was injected to form a solid, and then filtered. Drying at room temperature gave the title compound (yield: 62%). 1 H-NMR (400 MHz, CDCl 3 ) δ 3.52 (3H, s), 7.40-7.46 (1H, m), 7.50-7.58 (2H, m), 7.60-7.66 (2H, m), 8.12 (1H, s) )
<제조예 3 내지 제조예 12><Preparation Examples 3 to 12>
제조예 3 내지 제조예 12에서는 제조예 1과 실질적으로 동일한 방법으로 적절한 아민 유도체를 사용하여 제조하였다. Preparation Examples 3 to 12 were prepared in substantially the same manner as in Preparation Example 1 using appropriate amine derivatives.
제조예 3: 2-클로로-7-메틸-9-테트라하이드로티오피란-4-일-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-tetrahydrothiopyran-4-yl-7,9-dihydro-8H-purin-8-one}의 제조Preparation 3: 2-chloro-7-methyl-9-tetrahydrothiopyran-4-yl-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9-tetrahydrothiopyran- Preparation of 4-yl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000075
Figure PCTKR2022002310-appb-img-000075
수득률: 95 %; 1H-NMR (400MHz, CDCl3) δ 2.05-2.13 (2H, m), 2.72-2.82 (4H, m), 2.83-2.90 (2H, m), 3.44 (3H, s), 4.33 (1H, t), 8.01 (1H, s)Yield: 95%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.05-2.13 (2H, m), 2.72-2.82 (4H, m), 2.83-2.90 (2H, m), 3.44 (3H, s), 4.33 (1H, t) ), 8.01 (1H, s)
제조예 4: 2-클로로-7-메틸-9-스피로[3.3]헵탄-2-일-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-spiro[3.3]heptan-2-yl-7,9-dihydro-8H-purin-8-one}의 제조Preparation 4: 2-chloro-7-methyl-9-spiro [3.3] heptan-2-yl-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9-spiro [3.3] Preparation of heptan-2-yl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000076
Figure PCTKR2022002310-appb-img-000076
수득률: 91 %; 1H-NMR (400MHz, CDCl3) δ 1.84-1.91 (2H, m), 2.08-2.15 (4H, m), 2.36-2.42 (2H, m), 2.96-3.03 (2H, m), 3.42 (3H, s), 4.78-4.87 (1H, m), 7.98 (1H, s) Yield: 91%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.84-1.91 (2H, m), 2.08-2.15 (4H, m), 2.36-2.42 (2H, m), 2.96-3.03 (2H, m), 3.42 (3H) , s), 4.78-4.87 (1H, m), 7.98 (1H, s)
제조예 5: 2-클로로-9-(3-메톡시사이클로부틸)-7-메틸-7,9-디하이드로-8H-푸린-8-온 {2-chloro-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one}의 제조Preparation 5: 2-chloro-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one {2-chloro-9-(3-methoxycyclobutyl)- Preparation of 7-methyl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000077
Figure PCTKR2022002310-appb-img-000077
수득률: 56 %; 1H-NMR (400MHz, CDCl3) δ 2.44-2.51 (2H, m), 3.08-3.15 (2H, m), 3.31 (3H, s), 3.44 (3H, s), 4.29-4.34 (1H, m), 5.19-5.28 (1H, m), 8.01 (1H, s)Yield: 56%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.44-2.51 (2H, m), 3.08-3.15 (2H, m), 3.31 (3H, s), 3.44 (3H, s), 4.29-4.34 (1H, m) ), 5.19-5.28 (1H, m), 8.01 (1H, s)
제조예 6: 2-클로로-7-메틸-9-(2-옥사스피로[3.3]헵탄-6-일)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one}의 제조Preparation 6: 2-chloro-7-methyl-9- (2-oxaspiro [3.3] heptan-6-yl) -7,9-dihydro-8H-purin-8-one {2-chloro-7- Preparation of methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000078
Figure PCTKR2022002310-appb-img-000078
수득률: 86 %; 1H-NMR (400MHz, CDCl3) δ 2.64-2.70 (2H, m), 3.09-3.14 (2H, m), 3.38 (3H, s), 4.71-4.82 (5H, m), 7.97 (1H, s)Yield: 86%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.64-2.70 (2H, m), 3.09-3.14 (2H, m), 3.38 (3H, s), 4.71-4.82 (5H, m), 7.97 (1H, s) )
제조예 7: 2-클로로-7-메틸-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}의 제조Preparation 7: 2-chloro-7-methyl-9- (2-oxaspiro [3.5] nonan-7-yl) -7,9-dihydro-8H-purin-8-one {2-chloro-7- Preparation of methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000079
Figure PCTKR2022002310-appb-img-000079
수득률: 82 %; 1H-NMR (400MHz, CDCl3) δ 1.54-1.65 (2H, m), 1.72-1.81 (2H, m), 2.33 (4H, q), 3.43 (3H, s), 4.3 (1H, t), 4.40 (2H, s), 4.59 (2H, s), 8.00 (1H, s)Yield: 82%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.54-1.65 (2H, m), 1.72-1.81 (2H, m), 2.33 (4H, q), 3.43 (3H, s), 4.3 (1H, t), 4.40 (2H, s), 4.59 (2H, s), 8.00 (1H, s)
제조예 8: 2-클로로-7-메틸-9-(2-모폴리노에틸)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin-8-one}의 제조Preparation 8: 2-chloro-7-methyl-9- (2-morpholinoethyl) -7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9- (2 Preparation of -morpholinoethyl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000080
Figure PCTKR2022002310-appb-img-000080
수득률: 95 %; 1H-NMR (400MHz, CDCl3) δ 2.55 (4H, br), 2.75 (2H, t), 3.49 (3H, s), 3.63 (4H, t), 4.10 (2H, t), 8.03 (1H, s)Yield: 95%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.55 (4H, br), 2.75 (2H, t), 3.49 (3H, s), 3.63 (4H, t), 4.10 (2H, t), 8.03 (1H, s)
제조예 9: 2-클로로-7-메틸-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one}의 제조Preparation 9: 2-chloro-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9-morpholino-7,9-dihydro Preparation of -8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000081
Figure PCTKR2022002310-appb-img-000081
수득률: 89 %; 1H-NMR (400MHz, CDCl3) δ 3.44 (3H, s), 3.49 (4H, br), 3.92 (4H, t), 8.04 (1H, s)Yield: 89%; 1 H-NMR (400 MHz, CDCl 3 ) δ 3.44 (3H, s), 3.49 (4H, br), 3.92 (4H, t), 8.04 (1H, s)
제조예 10: 2-클로로-7-메틸-9-스피로[2.5]옥탄-6-일-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-spiro[2.5]octan-6-yl-7,9-dihydro-8H-purin-8-one}의 제조Preparation 10: 2-chloro-7-methyl-9-spiro [2.5] octan-6-yl-7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl-9-spiro [2.5] Preparation of octan-6-yl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000082
Figure PCTKR2022002310-appb-img-000082
수득률: 64 %; 1H-NMR (400MHz, CDCl3) δ 0.37 (4H, s), 1.00 (2H, d), 1.77 (2H, d), 1.96 (2H, t), 2.53 (2H, q), 3.44 (3H, s), 4.41 (1H, t), 7.99 (1H, s)Yield: 64%; 1 H-NMR (400 MHz, CDCl 3 ) δ 0.37 (4H, s), 1.00 (2H, d), 1.77 (2H, d), 1.96 (2H, t), 2.53 (2H, q), 3.44 (3H, s), 4.41 (1H, t), 7.99 (1H, s)
제조예 11: 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일메틸)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-ylmethyl)-7,9-dihydro-8H-purin-8-one}의 제조Preparation 11: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one {2-chloro-7-methyl Preparation of -9-(tetrahydro-2H-pyran-4-ylmethyl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000083
Figure PCTKR2022002310-appb-img-000083
수득률: 70 %; 1H-NMR (400MHz, CDCl3) δ 1.46 (2H, q), 1.54 (2H, m), 2.20 (1H, m), 3.35 (2H, t), 3.46 (3H, s), 3.86 (2H, d), 3.97 (2H, d), 8.02 (1H, s)Yield: 70%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.46 (2H, q), 1.54 (2H, m), 2.20 (1H, m), 3.35 (2H, t), 3.46 (3H, s), 3.86 (2H, d), 3.97 (2H, d), 8.02 (1H, s)
제조예 12: 2-클로로-9-(2-메톡시에틸)-7-메틸-7,9-디하이드로-8H-푸린-8-온 {2-chloro-9-(2-methoxyethyl)-7-methyl-7,9-dihydro-8H-purin-8-one}의 제조Preparation 12: 2-chloro-9-(2-methoxyethyl)-7-methyl-7,9-dihydro-8H-purin-8-one {2-chloro-9-(2-methoxyethyl)-7 Preparation of -methyl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000084
Figure PCTKR2022002310-appb-img-000084
수득률: 35 %; 1H-NMR (400MHz, CDCl3) δ 3.35 (3H, s), 3.46 (3H, s), 3.76 (2H, t), 4.16 (2H, t), 8.01 (1H, s)Yield: 35%; 1 H-NMR (400 MHz, CDCl 3 ) δ 3.35 (3H, s), 3.46 (3H, s), 3.76 (2H, t), 4.16 (2H, t), 8.01 (1H, s)
제조예 13: 2-클로로-7-에틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-7,9-dihydro-8H-purin-8-one}의 제조Preparation 13: 2-chloro-7-ethyl-9- (tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purin-8-one {2-chloro-7-ethyl- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000085
Figure PCTKR2022002310-appb-img-000085
0 ℃에서 제조예 1의 단계 2에서 제조한 2-클로로-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 50 mg을 디메틸포름아미드에 녹인 후 60 % 소듐하이드라이드 10 mg을 투입하고, 상온에서 에틸 아이오다이드 40 mg을 투입하였다. 상온에서 16 시간 동안 교반한 후 정제수를 주입하였고, 생성된 고체를 여과하여 표제 화합물을 수득하였다(수득률: 56 %). 1H-NMR (400MHz, CDCl3) δ 1.38 (3H, t), 1.72 (2H, dd), 2.69-2.80 (2H, m), 3.53 (2H, t), 3.94 (2H, q), 4.13 (2H, dd), 4.55-4.63 (1H, m), 8.03 (1H, s)50 mg of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one prepared in Step 2 of Preparation Example 1 at 0 ° C. in dimethylform After dissolving in amide, 10 mg of 60% sodium hydride was added, and 40 mg of ethyl iodide was added at room temperature. After stirring at room temperature for 16 hours, purified water was injected, and the resulting solid was filtered to obtain the title compound (yield: 56 %). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.38 (3H, t), 1.72 (2H, dd), 2.69-2.80 (2H, m), 3.53 (2H, t), 3.94 (2H, q), 4.13 ( 2H, dd), 4.55-4.63 (1H, m), 8.03 (1H, s)
제조예 14: 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온 {2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione}의 제조Preparation 14: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purine-8-thione {2-chloro-7-methyl- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione}
단계 1: 2-클로로-9-테트라하이드로-2H-피란-4-일-7,9-디하이드로-8H-푸린-8-티온 {2-chloro-9-tetrahydro-2H-pyran-4-yl-7,9-dihydro-8H-purine-8-thione}의 제조Step 1: 2-chloro-9-tetrahydro-2H-pyran-4-yl-7,9-dihydro-8H-purine-8-thione {2-chloro-9-tetrahydro-2H-pyran-4-yl Preparation of -7,9-dihydro-8H-purine-8-thione}
Figure PCTKR2022002310-appb-img-000086
Figure PCTKR2022002310-appb-img-000086
제조예 1의 단계 1에서 제조한 2-클로로-4-(테트라하이드로-2H-피란-4-일)피리미딘-4,5-디아민 100 mg 및 티오카보닐디이미다졸 180 mg을 아세토니트릴 2 ml에 넣은 후 마이크로웨이브장치를 사용하여 3 시간 동안 환류 교반하였다. 반응 종료 후, 용매를 농축하고, 에틸아세테이트 10 ml와 정제수 10 ml를 주입하였다. 에틸아세테이트 층을 분리하여 마그네슘설페이트를 처리한 후, 농축하였다. Prep-HPLC로 정제하여 표제 화합물을 수득하였다(수득률: 27 %). 1H-NMR (400MHz, CDCl3) δ 1.77 (2H, dd), 2.77-2.87 (2H, m), 3.53-3.60 (2H, m), 4.11 (2H, dd), 5.24-5.32 (1H, m), 8.27 (1H, s)100 mg of 2-chloro-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine and 180 mg of thiocarbonyldiimidazole prepared in Step 1 of Preparation Example 1 were mixed with 2 ml of acetonitrile After putting it in the microwave, it was stirred under reflux for 3 hours. After completion of the reaction, the solvent was concentrated, and 10 ml of ethyl acetate and 10 ml of purified water were injected. The ethyl acetate layer was separated, treated with magnesium sulfate, and then concentrated. Purification by Prep-HPLC gave the title compound (yield: 27%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.77 (2H, dd), 2.77-2.87 (2H, m), 3.53-3.60 (2H, m), 4.11 (2H, dd), 5.24-5.32 (1H, m ), 8.27 (1H, s)
단계 2: 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온 {2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione}제조Step 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione {2-chloro-7-methyl-9 -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione} production
Figure PCTKR2022002310-appb-img-000087
Figure PCTKR2022002310-appb-img-000087
0 ℃에서 단계 1에서 제조된 2-클로로-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온 30 mg을 디메틸포름아미드에 녹인 후, 60 % 소듐하이드라이드 10 mg을 투입하여 10 분간 교반한 후, 아이오도메탄 50 mg을 투입하였다. 4 시간 후 에틸아세테이트 10 ml와 정제수 10 ml를 주입한 후 에틸아세테이트 층을 분리하여 농축하였다. Prep-HPLC로 정제하여 표제 화합물을 수득하였다(수득률: 98 %). 1H-NMR (400MHz, CDCl3) δ 1.80 (2H, dd), 2.79-2.89 (5H, m), 3.56 (2H, t), 4.17 (2H, dd), 4.51-4.60(1H, m), 8.73 (1H, s)After dissolving 30 mg of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione prepared in step 1 at 0° C. in dimethylformamide, , 10 mg of 60% sodium hydride was added and stirred for 10 minutes, and then 50 mg of iodomethane was added. After 4 hours, 10 ml of ethyl acetate and 10 ml of purified water were injected, and the ethyl acetate layer was separated and concentrated. Purification by Prep-HPLC gave the title compound (yield: 98%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.80 (2H, dd), 2.79-2.89 (5H, m), 3.56 (2H, t), 4.17 (2H, dd), 4.51-4.60 (1H, m), 8.73 (1H, s)
제조예 15: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Preparation 15: 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione {2-chloro-5-methyl Preparation of -8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
단계 1: 2-클로로-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {2-chloro-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Step 1: 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione {2-chloro-8-(tetrahydro-2H-pyran) Preparation of -4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000088
Figure PCTKR2022002310-appb-img-000088
제조예 1의 단계 1에서 제조한 2-클로로-4-(테트라하이드로-2H-피란-4-일)피리미딘-4,5-디아민 30 mg을 디클로로메탄 2 mL에 넣고 0 ℃로 냉각하였다. 트리에틸아민 40 mg을 주입하고, 에틸클로로옥소아세테이트 16 mg을 주입하였다. 상온에서 2 시간 동안 교반한 후 4 시간 동안 환류 교반하였다. 반응 종결 후 상온으로 냉각하고 감압 농축하였다. MPLC로 정제하여 표제 화합물을 수득하였다(수득률: 70 %). 1H-NMR (400MHz, CD3OD) δ 1.63-1.66 (2H, m), 2.89-3.01 (2H, m), 3.57-3.63 (2H, m), 3.96-4.12 (2H, m), 5.43-4.59 (1H, m), 8.39 (1H, s)30 mg of 2-chloro-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine prepared in Step 1 of Preparation Example 1 was added to 2 mL of dichloromethane and cooled to 0 °C. 40 mg of triethylamine was injected, and 16 mg of ethylchlorooxoacetate was injected. After stirring at room temperature for 2 hours, the mixture was stirred under reflux for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. Purification by MPLC gave the title compound (yield: 70%). 1 H-NMR (400 MHz, CD 3 OD) δ 1.63-1.66 (2H, m), 2.89-3.01 (2H, m), 3.57-3.63 (2H, m), 3.96-4.12 (2H, m), 5.43 4.59 (1H, m), 8.39 (1H, s)
단계 2: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Step 2: 2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione {2-chloro-5-methyl- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000089
Figure PCTKR2022002310-appb-img-000089
단계 1에서 제조된 2-클로로-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 0.85 g을 디메틸포름아미드 3 mL에 넣고 0 ℃로 냉각하였다. 60 % 소듐하이드라이드 0.24 g을 분할 투입하고, 아이오도메탄 1.28 g을 서서히 주입하였다. 0 ℃에서 1 시간 동안 교반 후 상온에서 2 시간 동안 더 교반하였다. 반응 종료 후 정제수 20 mL을 주입한 후, 생성된 고체를 여과하고 실온에서 감압 건조하여 표제 화합물을 수득하였다(수득률: 60 %). 1H-NMR (400MHz, CDCl3) δ 1.60-1.63 (2H, m), 2.92-3.02 (2H, m), 3.54-3.61 (2H, m), 3.66 (3H, s), 4.12-4.16 (2H, m), 5.41-5.49 (1H, m), 8.29 (1H, s)0.85 g of 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione prepared in step 1 was added to 3 mL of dimethylformamide and 0 It was cooled to °C. 0.24 g of 60% sodium hydride was added in portions, and 1.28 g of iodomethane was slowly injected. After stirring at 0 °C for 1 hour, the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, 20 mL of purified water was injected, and the resulting solid was filtered and dried under reduced pressure at room temperature to obtain the title compound (yield: 60%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.60-1.63 (2H, m), 2.92-3.02 (2H, m), 3.54-3.61 (2H, m), 3.66 (3H, s), 4.12-4.16 (2H) , m), 5.41-5.49 (1H, m), 8.29 (1H, s)
<제조예 16 내지 제조예 21><Preparation Examples 16 to 21>
제조예 16 내지 제조예 21에서는 제조예 15와 실질적으로 동일한 방법으로 적절한 아민 유도체를 사용하여 제조하였다.Preparation Examples 16 to 21 were prepared using an appropriate amine derivative in substantially the same manner as in Preparation Example 15.
제조예 16: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일-메틸)프테리딘-6,7-디온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl-methyl)pteridine-6,7-dione}의 제조Preparation 16: 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl-methyl) pteridine-6,7-dione {2-chloro-5-methyl-8- (tetrahydro Preparation of -2H-pyran-4-yl-methyl)pteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000090
Figure PCTKR2022002310-appb-img-000090
수득률: 70 %; 1H-NMR (400MHz, CDCl3) δ 1.51-1.56 (4H, m), 2.13-2.24 (1H, m), 3.29-3.38 (2H, m), 3.67 (3H, s), 3.95-3.99 (2H, m), 4.28-4.30 (2H, m), 8.39 (1H, s)Yield: 70%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.51-1.56 (4H, m), 2.13-2.24 (1H, m), 3.29-3.38 (2H, m), 3.67 (3H, s), 3.95-3.99 (2H) , m), 4.28-4.30 (2H, m), 8.39 (1H, s)
제조예 17: 2-클로로-8-사이클로헥실-5-메틸-프테리딘-6,7-디온 {2-chloro-8-cyclohexyl-5-methyl-pteridine-6,7-dione}의 제조Preparation 17: Preparation of 2-chloro-8-cyclohexyl-5-methyl-pteridine-6,7-dione {2-chloro-8-cyclohexyl-5-methyl-pteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000091
Figure PCTKR2022002310-appb-img-000091
수득률: 93 %; 1H-NMR (400MHz, CDCl3) δ 1.34 (1H, t), 1.46 (2H, q), 1.71 (3H, t), 1.92 (2H, d), 2.57 (2H, q), 3.64 (3H, s), 5.18 (1H, t), 8.35 (1H, s)Yield: 93%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34 (1H, t), 1.46 (2H, q), 1.71 (3H, t), 1.92 (2H, d), 2.57 (2H, q), 3.64 (3H, s), 5.18 (1H, t), 8.35 (1H, s)
제조예 18: 2-클로로-8-사이클로펜틸-5-메틸-프테리딘-6,7-디온 {2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione}의 제조Preparation 18: Preparation of 2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione {2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000092
Figure PCTKR2022002310-appb-img-000092
수득률: 86 %; 1H-NMR (400MHz, CDCl3) δ 1.69 (2H, m), 1.97 (2H, q), 2.07-2.25 (4H, m), 3.65 (3H, s), 5.71 (1H, q), 8.37 (1H, s)Yield: 86%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.69 (2H, m), 1.97 (2H, q), 2.07-2.25 (4H, m), 3.65 (3H, s), 5.71 (1H, q), 8.37 ( 1H, s)
제조예 19: 2-클로로-5-메틸-8-(2-옥사스피로[3.5]노난-7-일)프테리딘-6,7-디온 {2-chloro-5-methyl-8-(2-oxaspiro[3.5]nonan-7-yl)pteridine-6,7-dione}의 제조Preparation 19: 2-chloro-5-methyl-8- (2-oxaspiro [3.5] nonan-7-yl) pteridine-6,7-dione {2-chloro-5-methyl-8- (2 Preparation of -oxaspiro[3.5]nonan-7-yl)pteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000093
Figure PCTKR2022002310-appb-img-000093
수득률: 48 %; 1H-NMR (400MHz, CDCl3) δ 1.61-1.69 (4H, m), 2.32 (2H, d), 2.60 (2H, q), 3.64 (3H, s), 4.40 (2H, s), 4.60 (2H, s), 5.16 (1H, t), 8.37 (1H, s)Yield: 48%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.61-1.69 (4H, m), 2.32 (2H, d), 2.60 (2H, q), 3.64 (3H, s), 4.40 (2H, s), 4.60 ( 2H, s), 5.16 (1H, t), 8.37 (1H, s)
제조예 20: 2-클로로-8-(4,4-디플루오로사이클로헥실)-5-메틸-프테리딘-6,7-디온 {2-chloro-8-(4,4-difluorocyclohexyl)-5-methyl-pteridine-6,7-dione}의 제조Preparation 20: 2-chloro-8- (4,4-difluorocyclohexyl) -5-methyl-pteridine-6,7-dione {2-chloro-8- (4,4-difluorocyclohexyl) - Preparation of 5-methyl-pteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000094
Figure PCTKR2022002310-appb-img-000094
수득률: 62 %; 1H-NMR (400MHz, CDCl3) δ 1.74-1.77 (2H, m), 1.88-2.05 (2H, m), 2.26-2.32 (2H, m), 2.92-3.01 (2H, m), 3.65 (3H, s), 5.26-5.34 (1H, m), 8.39 (1H, s)Yield: 62%; 1 H-NMR (400MHz, CDCl 3 ) δ 1.74-1.77 (2H, m), 1.88-2.05 (2H, m), 2.26-2.32 (2H, m), 2.92-3.01 (2H, m), 3.65 (3H) , s), 5.26-5.34 (1H, m), 8.39 (1H, s)
제조예 21: 2-클로로-8-사이클로부틸-5-메틸-프테리딘-6,7-디온 {2-chloro-8-cyclobutyl-5-methyl-pteridine-6,7-dione}의 제조Preparation 21: Preparation of 2-chloro-8-cyclobutyl-5-methyl-pteridine-6,7-dione {2-chloro-8-cyclobutyl-5-methyl-pteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000095
Figure PCTKR2022002310-appb-img-000095
수득률: 34 %; 1H-NMR (400MHz, CDCl3) δ 1.77 (2H, m), 2.30 (2H, q), 2.96 (2H, q), 5.54 (1H, q), 8.41 (1H, s)Yield: 34%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.77 (2H, m), 2.30 (2H, q), 2.96 (2H, q), 5.54 (1H, q), 8.41 (1H, s)
제조예 22: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Preparation 22: 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl) -7,8-dihydropteridin-6 (5H) -one {2-chloro-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
단계 1: 에틸 (테트라하이드로-2H-피란-4-일)글리시네이트 {ethyl (tetrahydro-2H-pyran-4-yl)glycinate}의 제조Step 1: Preparation of ethyl (tetrahydro-2H-pyran-4-yl)glycinate {ethyl (tetrahydro-2H-pyran-4-yl)glycinate}
Figure PCTKR2022002310-appb-img-000096
Figure PCTKR2022002310-appb-img-000096
4-아미노테트라하이드로피란 5 g, 에틸 클로로아세테이트 6.06 g 및 트리에틸아민 10.003 g을 아세토니트릴 20 mL에 투입하여 16 시간 동안 환류 교반하였다. 반응 종료 후 상온으로 냉각하였고, 에틸아세테이트 100 mL, 정제수 100 mL을 주입하여 에틸아세테이트 층을 분리하였다. 에틸아세테이트 층을 소듐설페이트 처리한 후, 여과하고 농축하여 표제 화합물를 수득하였다(수득률: 72 %). 1H-NMR (400MHz, CDCl3) δ 1.24-1.32 (3H, m), 1.39-1.49 (2H, m), 1.77-1.82 (2H, m), 2.71-2.73 (1H, m), 3.36-3.42 (2H, m), 3.44 (2H, s), 3.95-4.00 (2H, m), 4.17-4.23 (2H, m)5 g of 4-aminotetrahydropyran, 6.06 g of ethyl chloroacetate, and 10.003 g of triethylamine were added to 20 mL of acetonitrile, and the mixture was stirred under reflux for 16 hours. After completion of the reaction, it was cooled to room temperature, and 100 mL of ethyl acetate and 100 mL of purified water were injected to separate the ethyl acetate layer. The ethyl acetate layer was treated with sodium sulfate, filtered and concentrated to obtain the title compound (yield: 72 %). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.32 (3H, m), 1.39-1.49 (2H, m), 1.77-1.82 (2H, m), 2.71-2.73 (1H, m), 3.36-3.42 (2H, m), 3.44 (2H, s), 3.95-4.00 (2H, m), 4.17-4.23 (2H, m)
단계 2: 에틸 N-(2-클로로-5-니트로피리미딘-4-일)-N-(테트라하이드로-2H-피란-4-일)글리시네이트 {ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate}의 제조Step 2: Ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate {ethyl N-(2-chloro-5 Preparation of -nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate}
Figure PCTKR2022002310-appb-img-000097
Figure PCTKR2022002310-appb-img-000097
단계 1에서 제조된 에틸 (테트라하이드로-2H-피란-4-일)글리시네이트 3.2 g, 2,4-디클로로-5-니트로피리미딘 3.32 g 및 포타슘카보네이트 4.72 g을 아세톤 80 mL에 넣고 상온에서 16 시간 동안 교반하였다. 감압 농축한 후 에틸아세테이트 100 ml와 정제수 100 ml를 주입하고 에틸아세테이트 층을 분리하였다. 소듐설페이트 처리한 후, 여과하고 농축하였다. MPLC로 정제하여 표제 화합물를 수득하였다(수득률: 73 %). 1H-NMR (400MHz, CDCl3) δ 1.65-1.75 (2H, m), 2.04-2.08 (2H, m), 3.56-3.62 (2H, m), 4.01-4.06 (2H, m), 4.41-4.50 (1H, m), 8.32-8.33 (1H, m), 9.06 (1H, s)3.2 g of ethyl (tetrahydro-2H-pyran-4-yl)glycinate prepared in step 1, 3.32 g of 2,4-dichloro-5-nitropyrimidine, and 4.72 g of potassium carbonate were placed in 80 mL of acetone at room temperature stirred for 16 hours. After concentration under reduced pressure, 100 ml of ethyl acetate and 100 ml of purified water were injected, and the ethyl acetate layer was separated. After treatment with sodium sulfate, it was filtered and concentrated. Purification by MPLC gave the title compound (yield: 73%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.65-1.75 (2H, m), 2.04-2.08 (2H, m), 3.56-3.62 (2H, m), 4.01-4.06 (2H, m), 4.41-4.50 (1H, m), 8.32-8.33 (1H, m), 9.06 (1H, s)
단계 3: 2-클로로-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-chloro-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Step 3: 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one {2-chloro-8-(tetrahydro-2H- Preparation of pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000098
Figure PCTKR2022002310-appb-img-000098
단계 2에서 제조된 에틸 N-(2-클로로-5-니트로피리미딘-4-일)-N-(테트라하이드로-2H-피란-4-일)글리시네이트 1 g 및 철 파우더 0.486 g을 아세트산 14 mL에 넣고 반응기를 밀봉하였다. 마이크로웨이브장치에서 110 ℃, 1 시간 동안 반응시킨 후, 상온으로 냉각하고 셀라이트 여과하였다. 메탄올 10 mL로 세척하여 모은 여액에 디클로로메탄 100 mL, 포화 소듐하이드로젠카보네이트 수용액 150 mL을 주입한 후, 디클로로메탄 층을 분리하였다. 분리된 유기층을 마그네슘설페이트 처리하여 여과한 후 농축하였다. MPLC로 정제하여 표제 화합물을 수득하였다(수득률: 72 %). 1H-NMR (400MHz, CDCl3) δ 1.68-1.71 (2H, m), 1.82-1.92 (2H, m), 3.57-3.63 (2H, m), 4.09-4.13 (4H, m), 4.87-4.95 (1H, m), 7.64 (1H, s), 8.53 (1H, s)1 g of ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate prepared in step 2 and 0.486 g of iron powder It was added to 14 mL of acetic acid and the reactor was sealed. After reacting at 110° C. for 1 hour in a microwave device, it was cooled to room temperature and filtered through Celite. 100 mL of dichloromethane and 150 mL of saturated sodium hydrogen carbonate aqueous solution were injected into the filtrate collected by washing with 10 mL of methanol, and then the dichloromethane layer was separated. The separated organic layer was treated with magnesium sulfate, filtered, and then concentrated. Purification by MPLC gave the title compound (yield: 72%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.68-1.71 (2H, m), 1.82-1.92 (2H, m), 3.57-3.63 (2H, m), 4.09-4.13 (4H, m), 4.87-4.95 (1H, m), 7.64 (1H, s), 8.53 (1H, s)
단계 4: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Step 4: 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one {2-chloro-5-methyl Preparation of -8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000099
Figure PCTKR2022002310-appb-img-000099
단계 3에서 제조된 2-클로로-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 1.56 g을 디메틸포름아미드 29 mL에 넣은 후 0 ℃로 냉각하였다. 60 % 소듐하이드라이드 0.464 g을 분할 투입한 후, 10 분 동안 교반하였다. 아이오도메탄 0.442 g을 주입한 후 상온에서 2 시간 동안 교반하였다. 0 ℃에서 정제수 100 mL을 넣어 반응을 종결시킨 뒤 에틸아세테이트 100 mL로 2 ~ 3 회 추출하였다. 에틸아세테이트 층을 소듐설페이트로 건조시킨 뒤 여과하고 농축한 잔사물에 정제수를 첨가하였다. 생성된 고체를 여과하고, 열풍 건조기에서 45 ℃, 16 시간 동안 건조하여 표제 화합물을 수득하였다(수득률: 55 %). 1H-NMR (400MHz, CDCl3) δ 0.84-0.90 (2H, m), 1.67-1.70 (2H, m), 1.81-1.91 (2H, m), 3.33 (3H, s), 3.56-3.63 (2H, m), 4.07-4.11 (2H, m), 4.14 (2H, s), 4.87-4.95 (1H, m), 7.69 (1H, s)1.56 g of 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one prepared in step 3 was placed in 29 mL of dimethylformamide Then, it was cooled to 0 °C. After dividing 0.464 g of 60% sodium hydride, the mixture was stirred for 10 minutes. After injecting 0.442 g of iodomethane, the mixture was stirred at room temperature for 2 hours. After the reaction was terminated by adding 100 mL of purified water at 0 °C, extraction was performed 2-3 times with 100 mL of ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and purified water was added to the concentrated residue. The resulting solid was filtered and dried in a hot air dryer at 45° C. for 16 hours to obtain the title compound (yield: 55%). 1 H-NMR (400 MHz, CDCl 3 ) δ 0.84-0.90 (2H, m), 1.67-1.70 (2H, m), 1.81-1.91 (2H, m), 3.33 (3H, s), 3.56-3.63 (2H) , m), 4.07-4.11 (2H, m), 4.14 (2H, s), 4.87-4.95 (1H, m), 7.69 (1H, s)
<제조예 23 및 제조예 24><Preparation Example 23 and Preparation 24>
제조예 23 및 제조예 24에서는 제조예 22와 실질적으로 동일한 방법으로 적절한 유도체를 사용하여 제조하였다.Preparations 23 and 24 were prepared using an appropriate derivative in substantially the same manner as in Preparation Example 22.
제조예 23: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일메틸)-7,8-디하이드로프테리딘-6(5H)-온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydropteridin-6(5H)-one}의 제조Preparation 23: 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-ylmethyl) -7,8-dihydropteridin-6 (5H) -one {2-chloro-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000100
Figure PCTKR2022002310-appb-img-000100
수득률: 50 %; 1H-NMR (400MHz, CDCl3) δ 1.39-1.49 (2H, m), 1.57-1.61 (2H, m), 2.01-2.11 (1H, m), 3.33 (3H, s), 3.35-3.41 (2H, m), 3.50-3.52 (2H, m), 3.98-4.01 (2H, m), 4.22 (2H, s), 7.67 (1H, s)Yield: 50%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.39-1.49 (2H, m), 1.57-1.61 (2H, m), 2.01-2.11 (1H, m), 3.33 (3H, s), 3.35-3.41 (2H) , m), 3.50-3.52 (2H, m), 3.98-4.01 (2H, m), 4.22 (2H, s), 7.67 (1H, s)
제조예 24: 2-클로로-5,7-디메틸-8-테트라하이드로-2H-피란-4-일-7,8-디하이드로프테리딘-6(5H)-온 {2-chloro-5,7-dimethyl-8-tetrahydro-2H-pyran-4-yl-7,8-dihydropteridin-6(5H)-one}의 제조Preparation 24: 2-chloro-5,7-dimethyl-8-tetrahydro-2H-pyran-4-yl-7,8-dihydropteridin-6(5H)-one {2-chloro-5, Preparation of 7-dimethyl-8-tetrahydro-2H-pyran-4-yl-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000101
Figure PCTKR2022002310-appb-img-000101
수득률: 50 %; 1H-NMR (400MHz, CDCl3) δ 1.37-1.39 (3H, m), 1.64-1.68 (1H, m), 1.83-1.84 (1H, m), 2.03-2.09 (1H, m), 2.43 (1H, bs), 3.33 (3H, s), 3.53-3.60 (2H, m), 4.07-4.11 (2H, m), 4.36-4.41 (1H, m), 4.46-4.64 (1H, m), 7.76 (1H, s)Yield: 50%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.37-1.39 (3H, m), 1.64-1.68 (1H, m), 1.83-1.84 (1H, m), 2.03-2.09 (1H, m), 2.43 (1H) , bs), 3.33 (3H, s), 3.53-3.60 (2H, m), 4.07-4.11 (2H, m), 4.36-4.41 (1H, m), 4.46-4.64 (1H, m), 7.76 (1H) , s)
제조예 25: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Preparation 25: 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one {2-chloro-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
단계 1: 5-브로모-2-클로로-N-(테트라하이드로-2H-피란-4-일)피리미딘-4-아민 {5-bromo-2-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine}의 제조Step 1: 5-bromo-2-chloro-N- (tetrahydro-2H-pyran-4-yl) pyrimidin-4-amine {5-bromo-2-chloro-N- (tetrahydro-2H-pyran- Preparation of 4-yl)pyrimidin-4-amine}
Figure PCTKR2022002310-appb-img-000102
Figure PCTKR2022002310-appb-img-000102
5-브로모-2,4-디클로로피리미딘 5 g, 테트라하이드로-2H-피란-4-아민 2.5 mL 및 디이소프로필에틸아민 7.6 mL을 아세토니트릴 30 mL에 투입하였다. 상온에서 5 시간 교반한 후, 1N-염산 수용액 200 mL을 넣고 에틸아세테이트 200 mL로 2 ~ 3 회 추출하였다. 모아진 유기층을 마그네슘설페이트로 건조시킨 뒤 여과하고 농축하여 표제 화합물을 수득하였다(수득률: 97 %). 1H-NMR (400MHz, DMSO-d6) δ 1.69 (4H, m), 3.37 (2H, m), 3.88 (2H, m), 4.16 (1H, m), 7.40 (1H, d), 8.25 (1H, s)5 g of 5-bromo-2,4-dichloropyrimidine, 2.5 mL of tetrahydro-2H-pyran-4-amine and 7.6 mL of diisopropylethylamine were added to 30 mL of acetonitrile. After stirring at room temperature for 5 hours, 200 mL of 1N-hydrochloric acid aqueous solution was added, and extracted 2-3 times with 200 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to obtain the title compound (yield: 97%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.69 (4H, m), 3.37 (2H, m), 3.88 (2H, m), 4.16 (1H, m), 7.40 (1H, d), 8.25 ( 1H, s)
단계 2: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Step 2: 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one {2-chloro-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000103
Figure PCTKR2022002310-appb-img-000103
단계 1에서 제조된 5-브로모-2-클로로-N-(테트라하이드로-2H-피란-4-일)피리미딘-4-아민 2 g, 크로토닉산 5.885 g, 비스(벤조니트릴)디클로로팔라듐 131 mg, 트리스(2-메틸페닐)포스페인 104 mg 및 디이소프로필에틸아민 11.9 mL을 테트라하이드로푸란 30 mL에 넣고, 100 ℃에서 4 시간 동안 환류 교반한 후 상온으로 냉각시켰다. 무수아세트산 1.6 mL을 넣고 80 ℃에서 4 시간 동안 더 환류 교반한 후 셀라이트 여과하고 에틸아세테이트 100 mL로 세척하였다. 에틸아세테이트 층을 1N-염산 수용액으로 세척하고 수층을 에틸아세테이트 50 mL로 추출하였다. 모아진 유기층을 마그네슘설페이트로 건조시킨 뒤, 여과하고 농축하였다. 얻어진 잔사물을 MPLC로 정제하여 표제 화합물을 수득하였다(수득률: 63 %). 1H-NMR (400MHz, CDCl3) δ 1.54 (2H, d), 2.45 (3H, s), 3.04 (2H, m), 3.57 (2H, t), 4.10 (2H, dd), 5.54 (1H, t), 6.55 (1H, s), 8.75 (1H, s) 2 g of 5-bromo-2-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine prepared in step 1, 5.885 g of crotonic acid, bis(benzonitrile)dichloropalladium 131 mg, tris(2-methylphenyl)phosphate, 104 mg, and diisopropylethylamine 11.9 mL were placed in 30 mL of tetrahydrofuran, stirred under reflux at 100° C. for 4 hours, and then cooled to room temperature. After adding 1.6 mL of acetic anhydride and stirring under reflux at 80 °C for 4 hours, the mixture was filtered through Celite and washed with 100 mL of ethyl acetate. The ethyl acetate layer was washed with 1N-hydrochloric acid aqueous solution, and the aqueous layer was extracted with 50 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by MPLC to obtain the title compound (yield: 63%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.54 (2H, d), 2.45 (3H, s), 3.04 (2H, m), 3.57 (2H, t), 4.10 (2H, dd), 5.54 (1H, t), 6.55 (1H, s), 8.75 (1H, s)
<제조예 26 내지 제조예 31><Preparation Examples 26 to 31>
제조예 26 내지 제조예 31에서는 제조예 25와 실질적으로 동일한 방법으로 적절한 유도체를 사용하여 제조하였다.Preparation Examples 26 to 31 were prepared using appropriate derivatives in substantially the same manner as in Preparation Example 25.
제조예 26: 2-클로로-5-에틸-8-테트라하이드로-2H-피란-4-일-피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-5-ethyl-8-tetrahydro-2H-pyran-4-yl-pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Preparation 26: 2-chloro-5-ethyl-8-tetrahydro-2H-pyran-4-yl-pyrido [2,3-d] pyrimidin-7 (8H) -one {2-chloro-5- Preparation of ethyl-8-tetrahydro-2H-pyran-4-yl-pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000104
Figure PCTKR2022002310-appb-img-000104
수득률: 33 %; 1H-NMR (400MHz, CDCl3) δ 1.32 (3H, t), 1.54 (2H, d), 2.82 (2H, d), 3.05 (2H, q), 3.55 (2H, t), 4.11 (2H, d), 5.55 (1H, t), 6.57 (1H, s), 8.80 (1H, s)Yield: 33%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32 (3H, t), 1.54 (2H, d), 2.82 (2H, d), 3.05 (2H, q), 3.55 (2H, t), 4.11 (2H, d), 5.55 (1H, t), 6.57 (1H, s), 8.80 (1H, s)
제조예 27: 2-클로로-6-메틸-8-테트라하히드로-2H-피란-4-일-피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-6-methyl-8-tetrahydro-2H-pyran-4-yl-pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Preparation 27: 2-chloro-6-methyl-8-tetrahahydro-2H-pyran-4-yl-pyrido[2,3-d]pyrimidin-7(8H)-one {2-chloro-6 Preparation of -methyl-8-tetrahydro-2H-pyran-4-yl-pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000105
Figure PCTKR2022002310-appb-img-000105
수득률: 40 %; 1H-NMR (400MHz, CDCl3) δ 1.55 (2H, d), 2.24 (3H, s), 3.06 (2H, m), 3.58 (2H, t), 4.11 (2H, dd), 5.59 (1H, t), 7.48 (1H, s), 8.62 (1H, s)Yield: 40%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.55 (2H, d), 2.24 (3H, s), 3.06 (2H, m), 3.58 (2H, t), 4.11 (2H, dd), 5.59 (1H, t), 7.48 (1H, s), 8.62 (1H, s)
제조예 28: 2-클로로-8-(4,4-디플루오로사이클로헥실)-5-메틸-피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-8-(4,4-difluorocyclohexyl)-5-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Preparation 28: 2-chloro-8- (4,4-difluorocyclohexyl) -5-methyl-pyrido [2,3-d] pyrimidin-7 (8H) -one {2-chloro-8 Preparation of -(4,4-difluorocyclohexyl)-5-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000106
Figure PCTKR2022002310-appb-img-000106
수득률: 4 %; 1H-NMR (400MHz, CDCl3) δ 1.68-1.85 (4H, m), 2.23 (2H, m), 2.45 (3H, s), 3.03 (2H, m), 5.39 (1H, m), 6.54 (1H, s), 8.75 (1H, s)Yield: 4%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.68-1.85 (4H, m), 2.23 (2H, m), 2.45 (3H, s), 3.03 (2H, m), 5.39 (1H, m), 6.54 ( 1H, s), 8.75 (1H, s)
제조예 29: 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일 메틸)피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-ylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Preparation 29: 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl methyl) pyrido [2,3-d] pyrimidin-7 (8H) -one {2-chloro- Preparation of 5-methyl-8-(tetrahydro-2H-pyran-4-ylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000107
Figure PCTKR2022002310-appb-img-000107
수득률: 17 %; 1H-NMR (400MHz, CDCl3) δ 1.49 (4H, m), 2.04 (1H, m), 2.47 (3H, s), 3.29 (2H, m), 3.93 (2H, m), 4.31 (2H, d), 6.58 (1H, s), 8.76 (1H, s)Yield: 17%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.49 (4H, m), 2.04 (1H, m), 2.47 (3H, s), 3.29 (2H, m), 3.93 (2H, m), 4.31 (2H, d), 6.58 (1H, s), 8.76 (1H, s)
제조예 30: 2-클로로-8-사이클로헥실-5-메틸-피리도[2,3-d]피리미딘-7(8H)-온 {2-chloro-8-cyclohexyl-5-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Preparation 30: 2-chloro-8-cyclohexyl-5-methyl-pyrido [2,3-d] pyrimidin-7 (8H) -one {2-chloro-8-cyclohexyl-5-methyl-pyrido [ Preparation of 2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000108
Figure PCTKR2022002310-appb-img-000108
수득률: 11 %; 1H-NMR (400MHz, CDCl3) δ 1.34-1.90 (8H, m), 2.43 (3H, s), 2.67 (2H, m), 5.30 (1H, m), 6.53 (1H, s), 8.72 (1H, s)Yield: 11%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.90 (8H, m), 2.43 (3H, s), 2.67 (2H, m), 5.30 (1H, m), 6.53 (1H, s), 8.72 ( 1H, s)
제조예 31: 4-(2-클로로-5-메틸-7-옥소-피리도[2,3-d]피리미딘-8(7H)-일)사이클로헥실 아세테이트 {4-(2-chloro-5-methyl-7-oxo-pyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl acetate}의 제조Preparation 31: 4- (2-chloro-5-methyl-7-oxo-pyrido [2,3-d] pyrimidin-8 (7H) -yl) cyclohexyl acetate {4- (2-chloro-5 Preparation of -methyl-7-oxo-pyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl acetate}
Figure PCTKR2022002310-appb-img-000109
Figure PCTKR2022002310-appb-img-000109
수득률: 11 %; 1H-NMR (400MHz, CDCl3) δ 1.56-1.70 (4H, m), 2.05 (3H, s), 2.13 (2H, d), 2.44 (3H, s), 2.86 (2H, q), 4.86 (1H, m), 5.34 (1H, m), 6.53 (1H, s), 8.73 (1H, s)Yield: 11%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.56-1.70 (4H, m), 2.05 (3H, s), 2.13 (2H, d), 2.44 (3H, s), 2.86 (2H, q), 4.86 ( 1H, m), 5.34 (1H, m), 6.53 (1H, s), 8.73 (1H, s)
제조예 32: 6-클로로-3-메틸-1-(테트라하이드로-2H-피란-4-일)-1H-피라졸로[3,4-d]피리미딘 {6-chloro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine}의 제조Preparation 32: 6-chloro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine {6-chloro-3-methyl-1 Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine}
Figure PCTKR2022002310-appb-img-000110
Figure PCTKR2022002310-appb-img-000110
1-(2,4-디클로로피리미딘-5-일)에탄-1-온 0.1 g을 테트라하이드로푸란 1.5 mL에 투입하였다. 트리에틸아민 0.146 mL을 주입한 후 (테트라하이드로-2H-피란-4-일)하이드라진 0.064 g을 천천히 주입하였다. 상온에서 16 시간 동안 교반한 후, 에틸아세테이트 10 ml와 정제수 10 ml를 주입하였다. 에틸아세테이트층을 분리하여 소듐설페이트 처리한 후, 여과하여 농축하였다. 농축된 잔사물을 MPLC로 정제하여 표제 화합물을 수득하였다(수득률: 38 %). 1H-NMR (400MHz, CDCl3) δ 1.90-1.93 (2H, m), 2.34-2.44 (2H, m), 2.63 (3H, s), 3.59-3.65 (2H, m), 4.13-4.17 (2H, m), 4.92-5.00 (1H, m), 8.93 (1H, s)0.1 g of 1-(2,4-dichloropyrimidin-5-yl)ethan-1-one was added to 1.5 mL of tetrahydrofuran. After 0.146 mL of triethylamine was injected, (tetrahydro-2H-pyran-4-yl) 0.064 g of hydrazine was slowly injected. After stirring at room temperature for 16 hours, 10 ml of ethyl acetate and 10 ml of purified water were injected. The ethyl acetate layer was separated, treated with sodium sulfate, filtered and concentrated. The concentrated residue was purified by MPLC to give the title compound (yield: 38 %). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.90-1.93 (2H, m), 2.34-2.44 (2H, m), 2.63 (3H, s), 3.59-3.65 (2H, m), 4.13-4.17 (2H) , m), 4.92-5.00 (1H, m), 8.93 (1H, s)
제조예 33: 6-클로로-1-(테트라하이드로-2H-피란-4-일)-1H-피라졸로[3,4-d]피리미딘 {6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine}의 제조Preparation 33: 6-chloro-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-d] pyrimidine {6-chloro-1- (tetrahydro-2H-pyran- Preparation of 4-yl)-1H-pyrazolo[3,4-d]pyrimidine}
Figure PCTKR2022002310-appb-img-000111
Figure PCTKR2022002310-appb-img-000111
제조예 32와 실질적으로 동일한 방법으로 2,4-디클로로피리미딘-5-카발데히드를 사용하여 제조하였다(수득률: 30 %). 1H-NMR (400MHz, CDCl3) δ 1.93-1.67 (2H, m), 2.34-2.44 (2H, m), 3.59-3.65 (2H, m), 4.13-4.16 (2H, m), 4.77-4.85 (1H, m), 7.90(1H, s), 8.79 (1H, s)It was prepared using 2,4-dichloropyrimidine-5-carbaldehyde in substantially the same manner as in Preparation Example 32 (yield: 30%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.93-1.67 (2H, m), 2.34-2.44 (2H, m), 3.59-3.65 (2H, m), 4.13-4.16 (2H, m), 4.77-4.85 (1H, m), 7.90 (1H, s), 8.79 (1H, s)
실시예 1: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 1: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)- Preparation of 7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000112
Figure PCTKR2022002310-appb-img-000112
상기 제조예 1에서 제조한 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 30 mg, 2,5-디메틸벤조[d]티아졸-6-아민 32 mg, 세슘카보네이트 73 mg, 팔라듐 아세테이트 3 mg 및 엑스포스 10 mg을 다이옥산 2 mL에 녹인 후 마이크로웨이브를 사용하여 130 ℃에서 30 분 동안 반응하였다. 셀라이트 여과하여 농축한 후, Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 11 %). 1H-NMR (400MHz, CDCl3) δ 1.73-1.77 (2H, m), 2.48 (3H, s), 2.75-2.86 (5H, m), 3.41 (3H, s), 3.52-3.58 (2H, m), 4.13-4.17 (2H, m), 4.52-4.60 (1H, m), 6.86-8.78 (4H, m)2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one prepared in Preparation Example 1 30 mg, 2,5 -Dimethylbenzo[d]thiazol-6-amine 32 mg, cesium carbonate 73 mg, palladium acetate 3 mg, and Expos 10 mg were dissolved in 2 mL of dioxane and then reacted at 130° C. for 30 minutes using a microwave. After concentration by celite filtration and purification by Prep-HPLC, the target compound was obtained (yield: 11 %). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73-1.77 (2H, m), 2.48 (3H, s), 2.75-2.86 (5H, m), 3.41 (3H, s), 3.52-3.58 (2H, m) ), 4.13-4.17 (2H, m), 4.52-4.60 (1H, m), 6.86-8.78 (4H, m)
<실시예 2 내지 실시예 31><Examples 2 to 31>
실시예 2 내지 실시예 31에서는 실시예 1과 실질적으로 동일한 방법으로 적절한 중간체와 아민을 사용하여 제조하였다.Examples 2 to 31 were prepared in substantially the same manner as in Example 1, using appropriate intermediates and amines.
실시예 2: 7-메틸-2-((6-메틸퀴놀린-7-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 2: 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one {7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one } manufacturing
Figure PCTKR2022002310-appb-img-000113
Figure PCTKR2022002310-appb-img-000113
수득률: 10 %; 1H-NMR (400MHz, CDCl3) δ 1.74-1.78 (2H, m), 2.57 (3H, s), 2.76-2.87 (2H, m), 3.43 (3H, s), 3.53-3.59 (2H, m), 4.13-4.17 (2H, m), 4.53-4.58 (1H, m), 7.01-9.10 (7H, m)Yield: 10%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74-1.78 (2H, m), 2.57 (3H, s), 2.76-2.87 (2H, m), 3.43 (3H, s), 3.53-3.59 (2H, m) ), 4.13-4.17 (2H, m), 4.53-4.58 (1H, m), 7.01-9.10 (7H, m)
실시예 3: 2-(벤조[d]티아졸-6-일아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 3: 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one {2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one} manufacture of
Figure PCTKR2022002310-appb-img-000114
Figure PCTKR2022002310-appb-img-000114
수득률: 10 %; 1H-NMR (400MHz, CDCl3) δ 1.74-1.78 (2H, m), 2.77-2.87 (2H, m), 3.42 (3H, s), 3.52-3.58 (2H, m), 4.14-4.18 (2H, m), 4.52-4.61 (1H, m), 7.32-8.86 (6H, m)Yield: 10%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74-1.78 (2H, m), 2.77-2.87 (2H, m), 3.42 (3H, s), 3.52-3.58 (2H, m), 4.14-4.18 (2H) , m), 4.52-4.61 (1H, m), 7.32-8.86 (6H, m)
실시예 4: 2-((5-히드록시나프탈렌-2-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 4: 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine -8-one {2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8- manufacture of one}
Figure PCTKR2022002310-appb-img-000115
Figure PCTKR2022002310-appb-img-000115
수득률: 12 %; 1H-NMR (400MHz, CD3OD) δ 1.78-1.81 (2H, m), 2.85-2.95 (2H, m), 3.36-3.42 (2H, m), 3.57-3.63 (2H, m), 4.55-4.61 (1H, m), 6.72-8.44 (8H, m)Yield: 12%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.78-1.81 (2H, m), 2.85-2.95 (2H, m), 3.36-3.42 (2H, m), 3.57-3.63 (2H, m), 4.55- 4.61 (1H, m), 6.72-8.44 (8H, m)
실시예 5: 7-메틸-2-((5-메틸-1H-인돌-6-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 5: 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H -Purin-8-one {7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro- Preparation of 8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000116
Figure PCTKR2022002310-appb-img-000116
수득률: 5 %; 1H-NMR (400MHz, CDCl3) δ 1.75-1.79 (2H, m), 2.45 (3H, s), 2.99-3.10 (2H, m), 3.41 (3H, s), 3.56-3.62 (2H, m), 4.18-4.22 (2H, m), 4.57-4.66 (1H, m), 6.43-8.77 (7H, m)Yield: 5%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.75-1.79 (2H, m), 2.45 (3H, s), 2.99-3.10 (2H, m), 3.41 (3H, s), 3.56-3.62 (2H, m) ), 4.18-4.22 (2H, m), 4.57-4.66 (1H, m), 6.43-8.77 (7H, m)
실시예 6: 2-((5-클로로벤조[d]옥사졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 6: 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro -8H-purin-8-one {2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Preparation of dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000117
Figure PCTKR2022002310-appb-img-000117
수득률: 12 %; 1H-NMR (400MHz, CD3OD) δ 1.78-1.81 (2H, m), 2.74-2.85 (2H, m), 3.45 (3H, s), 3.56-3.62 (2H, m), 4.16-4.20 (2H, m), 4.56-4.62 (1H, m), 7.83-8.97 (4H, m)Yield: 12%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.78-1.81 (2H, m), 2.74-2.85 (2H, m), 3.45 (3H, s), 3.56-3.62 (2H, m), 4.16-4.20 ( 2H, m), 4.56-4.62 (1H, m), 7.83-8.97 (4H, m)
실시예 7: 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 7: 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one {2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)- Preparation of 7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000118
Figure PCTKR2022002310-appb-img-000118
수득률: 5 %; 1H-NMR (400MHz, CD3OD) δ 1.75-1.78 (2H, m), 2.45 (3H, s), 2.69-2.82 (5H, m), 3.41 (3H, s), 3.54-3.61 (2H, m), 4.10-4.14 (2H, m), 4.51-4.57 (1H, m), 7.66-8.51 (3H, m)Yield: 5%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.75-1.78 (2H, m), 2.45 (3H, s), 2.69-2.82 (5H, m), 3.41 (3H, s), 3.54-3.61 (2H, m), 4.10-4.14 (2H, m), 4.51-4.57 (1H, m), 7.66-8.51 (3H, m)
실시예 8: 2,2-디메틸-7-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-2H-벤조[b][1,4]옥사진-3(4H)-온 {2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one}의 제조Example 8: 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one {2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H) Preparation of -pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one}
Figure PCTKR2022002310-appb-img-000119
Figure PCTKR2022002310-appb-img-000119
수득률: 7 %; 1H-NMR (400MHz, CD3OD) δ 1.53 (6H, s), 1.75-1.78 (2H, m), 2.72-2.83 (2H, m), 3.41 (3H, s), 3.54-3.60 (2H, m), 4.50-4.56 (1H, m), 6.79-7.90 (5H, m)Yield: 7%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.53 (6H, s), 1.75-1.78 (2H, m), 2.72-2.83 (2H, m), 3.41 (3H, s), 3.54-3.60 (2H, m), 4.50-4.56 (1H, m), 6.79-7.90 (5H, m)
실시예 9: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 9: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran Preparation of -4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000120
Figure PCTKR2022002310-appb-img-000120
수득률: 10 %; 1H-NMR (400MHz, CDCl3) δ 1.70-1.73 (2H, m), 2.24 (3H, s), 2.71-2.81 (2H, m), 3.37 (3H, s), 3.50-3.56 (2H, m), 4.10-4.14 (2H, m), 4.48-4.54 (1H, m), 5.93-7.82 (6H, m)Yield: 10%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.70-1.73 (2H, m), 2.24 (3H, s), 2.71-2.81 (2H, m), 3.37 (3H, s), 3.50-3.56 (2H, m) ), 4.10-4.14 (2H, m), 4.48-4.54 (1H, m), 5.93-7.82 (6H, m)
실시예 10: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 10: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-( Preparation of tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000121
Figure PCTKR2022002310-appb-img-000121
수득률: 30 %; 1H-NMR (400MHz, CDCl3) δ 1.76-1.79 (2H, m), 2.60 (3H, s), 2.80-2.87 (2H, m), 3.45 (3H, s), 3.54-3.60 (2H, m), 4.15-4.19 (2H, m), 4.55-4.63 (1H, m), 7.07-9.08 (4H, m)Yield: 30%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.76-1.79 (2H, m), 2.60 (3H, s), 2.80-2.87 (2H, m), 3.45 (3H, s), 3.54-3.60 (2H, m) ), 4.15-4.19 (2H, m), 4.55-4.63 (1H, m), 7.07-9.08 (4H, m)
실시예 11: 2-((4,7-디메틸-2-옥소-2H-크로멘-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 11: 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one {2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000122
Figure PCTKR2022002310-appb-img-000122
수득률: 13 %; 1H-NMR (400MHz, CDCl3) δ 1.72-1.75 (2H, m), 2.44 (3H, s), 2.48 (3H, s), 2.71-2.82 (2H, m), 3.41 (3H, s), 3.50-3.56 (2H, m), 4.10-4.13 (2H, m), 4.53-4.59 (1H, m), 6.27-8.34 (5H, m)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72-1.75 (2H, m), 2.44 (3H, s), 2.48 (3H, s), 2.71-2.82 (2H, m), 3.41 (3H, s), 3.50-3.56 (2H, m), 4.10-4.13 (2H, m), 4.53-4.59 (1H, m), 6.27-8.34 (5H, m)
실시예 12: 7-메틸-2-((4-메틸-6-(4-메틸-1H-이미다졸-1-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 12: 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000123
Figure PCTKR2022002310-appb-img-000123
수득률: 6 %; 1H-NMR (400MHz, CDCl3) δ 1.71-1.75 (2H, m), 2.30 (3H, s), 2.42 (3H, s), 2.70-2.80 (3H, m), 3.41 (3H, s), 3.51-3.67 (2H, m), 4.11-4.15 (2H, m), 4.50-4.58 (1H, m), 6.59-9.04 (6H, m)Yield: 6%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.71-1.75 (2H, m), 2.30 (3H, s), 2.42 (3H, s), 2.70-2.80 (3H, m), 3.41 (3H, s), 3.51-3.67 (2H, m), 4.11-4.15 (2H, m), 4.50-4.58 (1H, m), 6.59-9.04 (6H, m)
실시예 13: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리노니트릴 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinonitrile}의 제조Example 13: 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino) picolinonitrile {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Preparation of amino) picolinonitrile}
Figure PCTKR2022002310-appb-img-000124
Figure PCTKR2022002310-appb-img-000124
수득률: 29 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.41 (3H, s), 2.74 (2H, m), 3.43 (3H, s), 3.55 (2H, t), 4.15 (3H, dd), 4.13 (2H, dd), 4.52-4.60 (1H, m), 6.84-9.75 (4H, m)Yield: 29%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.41 (3H, s), 2.74 (2H, m), 3.43 (3H, s), 3.55 (2H, t), 4.15 (3H, dd), 4.13 (2H, dd), 4.52-4.60 (1H, m), 6.84-9.75 (4H, m)
실시예 14: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 14: 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)picolinamide {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Preparation of amino)picolinamide}
Figure PCTKR2022002310-appb-img-000125
Figure PCTKR2022002310-appb-img-000125
단계 1: 5-아미노-4-메틸-피콜린아미드 (5-amino-4-methyl-picolinamide)의 제조Step 1: Preparation of 5-amino-4-methyl-picolinamide (5-amino-4-methyl-picolinamide)
Figure PCTKR2022002310-appb-img-000126
Figure PCTKR2022002310-appb-img-000126
5-아미노-4-메틸피콜리노니트릴 100 mg 및 소듐하이드록사이드 43 mg을 반응기에 넣고 에탄올 1.5 mL, 정제수 1.5 mL을 주입하였다. 50 ℃에서 4 시간 동안 교반한 후, 에틸아세테이트 10 ml와 정제수 10 ml를 주입하였다. 에틸아세테이트 층을 분리하여 마그네슘설페이트 처리한 후, 여과하여 농축하였다. 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 44 %). 1H-NMR (400MHz, CDCl3) δ 2.21 (3H, s), 2.43 (3H, s), 4.40 (2H, br), 7.90 (1H, s), 7.92 (1H, s)100 mg of 5-amino-4-methylpicolinonitrile and 43 mg of sodium hydroxide were placed in a reactor, and 1.5 mL of ethanol and 1.5 mL of purified water were injected. After stirring at 50° C. for 4 hours, 10 ml of ethyl acetate and 10 ml of purified water were injected. The ethyl acetate layer was separated, treated with magnesium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to obtain the target compound (yield: 44%). 1 H-NMR (400 MHz, CDCl 3 ) δ 2.21 (3H, s), 2.43 (3H, s), 4.40 (2H, br), 7.90 (1H, s), 7.92 (1H, s)
단계 2: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Step 2: 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )picolinamide {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) Preparation of picolinamide}
상기 단계 1에서 얻어진 5-아미노-4-메틸-피콜린아미드를 사용하여 실시예 1과 실질적으로 동일한 방법으로 목적 화합물을 제조하였다(수득률: 11 %). 1H-NMR (400MHz, CDCl3) δ 1.74 (2H, d), 2.43 (3H, s), 2.76 (2H, m), 3.43 (3H, s), 3.55 (2H, t), 4.15 (3H, dd), 4.53-4.59 (1H, m), 5.52 (1H, s), 6.83-9.51 (5H, m)A target compound was prepared in substantially the same manner as in Example 1 using 5-amino-4-methyl-picolinamide obtained in Step 1 (yield: 11%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, d), 2.43 (3H, s), 2.76 (2H, m), 3.43 (3H, s), 3.55 (2H, t), 4.15 (3H, dd), 4.53-4.59 (1H, m), 5.52 (1H, s), 6.83-9.51 (5H, m)
실시예 15: 메틸 5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)티오펜-2-카르복실레이트 {methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)thiophene-2-carboxylate}의 제조Example 15: Methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)thi Offene-2-carboxylate {methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) Preparation of thiophene-2-carboxylate}
Figure PCTKR2022002310-appb-img-000127
Figure PCTKR2022002310-appb-img-000127
수득률: 7 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.83 (2H, dq), 3.43 (3H, s), 3.55 (2H, t), 3.87 (3H, t), 4.16 (2H, dd), 4.55-4.63 (1H, m), 6.54-7.98 (4H, m)Yield: 7%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.83 (2H, dq), 3.43 (3H, s), 3.55 (2H, t), 3.87 (3H, t), 4.16 (2H, dd), 4.55-4.63 (1H, m), 6.54-7.98 (4H, m)
실시예 16: 메틸 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리네이트 {methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinate}의 제조Example 16: Methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)picolinate {methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2- Preparation of yl)amino)picolinate}
Figure PCTKR2022002310-appb-img-000128
Figure PCTKR2022002310-appb-img-000128
수득률: 29 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.43 (3H, s), 2.75 (2H, m), 3.42 (3H,s), 3.55 (2H, t), 4.00 (3H, s), 4.14 (2H, dd), 4.52-4.60 (1H, m), 6.84-9.66 (4H, m)Yield: 29%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.43 (3H, s), 2.75 (2H, m), 3.42 (3H,s), 3.55 (2H, t), 4.00 (3H, s), 4.14 (2H, dd), 4.52-4.60 (1H, m), 6.84-9.66 (4H, m)
실시예 17: N,4-디메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 17: N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- yl)amino)picolinamide {N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- Preparation of 2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000129
Figure PCTKR2022002310-appb-img-000129
실시예 16 화합물을 사용하여 하기 반응식을 수행하여 실시예 17의 화합물을 수득하였다.The compound of Example 17 was obtained by performing the following scheme using the compound of Example 16.
Figure PCTKR2022002310-appb-img-000130
Figure PCTKR2022002310-appb-img-000130
메틸 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리네이트 16.6 mg 및 1N-포타슘하이드록사이드 1 mL을 테트라하이드로푸란 1 mL 및 메탄올 1 mL인 혼합용매에 투입하고 50 ℃에서 2 시간 동안 교반하였다. 반응 종료후 에틸아세테이트와 1N-염산수용액을 주입한 후, 유기층을 분리하여 농축하였다. 얻어진 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린산 20 mg, 메틸아민 3 mg, 디아이소프로필에틸아민 0.056 mL 및 HATU 40 mg을 디메틸포름아미드 3 mL에 넣고, 16 시간 동안 상온 교반하였다. 반응물을 농축하고, Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 24 %). 1H-NMR (400MHz, CDCl3) δ 1.74 (2H, dd), 2.43 (3H, s), 2.76 (2H, m), 3.03 (3H, d), 3.42 (3H, s), 3.56 (2H, t), 4.15 (2H, dd), 4.52-4.60 (1H, m), 6.81-9.45 (4H, m)Methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)p 16.6 mg of cholinate and 1 mL of 1N-potassium hydroxide were added to a mixed solvent of 1 mL of tetrahydrofuran and 1 mL of methanol, and the mixture was stirred at 50° C. for 2 hours. After completion of the reaction, ethyl acetate and 1N-hydrochloric acid solution were injected, and the organic layer was separated and concentrated. Obtained 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)p 20 mg of cholic acid, 3 mg of methylamine, 0.056 mL of diisopropylethylamine and 40 mg of HATU were placed in 3 mL of dimethylformamide, and the mixture was stirred at room temperature for 16 hours. The reaction was concentrated and purified by Prep-HPLC to obtain the desired compound (yield: 24%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, dd), 2.43 (3H, s), 2.76 (2H, m), 3.03 (3H, d), 3.42 (3H, s), 3.56 (2H, t), 4.15 (2H, dd), 4.52-4.60 (1H, m), 6.81-9.45 (4H, m)
실시예 18: 7-메틸-2-((4-메틸-6-(메틸티오)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 18: 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) Preparation of -7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000131
Figure PCTKR2022002310-appb-img-000131
수득률: 18 %; 1H-NMR (400MHz, CDCl3) δ 1.71 (2H, dd), 2.29 (3H, s), 2.57 (3H, s), 2.73 (2H, dq), 3.39 (3H, s), 3.53 (2H, t), 4.12 (2H, dd), 4.52 (1H, m), 6.45-8.95 (4H, m)Yield: 18%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.71 (2H, dd), 2.29 (3H, s), 2.57 (3H, s), 2.73 (2H, dq), 3.39 (3H, s), 3.53 (2H, t), 4.12 (2H, dd), 4.52 (1H, m), 6.45-8.95 (4H, m)
실시예 19: 7-메틸-2-((4-메틸-6-(트리플루오로메틸)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 19: 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- Preparation of yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000132
Figure PCTKR2022002310-appb-img-000132
수득률: 21 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.40 (3H, s), 2.77 (3H, s), 3.41 (3H, d), 3.54 (2H, t), 4.13 (2H, dd), 4.54 (1H, m), 6.61-9.27 (5H, m)Yield: 21%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.40 (3H, s), 2.77 (3H, s), 3.41 (3H, d), 3.54 (2H, t), 4.13 (2H, dd), 4.54 (1H, m), 6.61-9.27 (5H, m)
실시예 20: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one}의 제조Example 20: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8 -one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one} Produce
Figure PCTKR2022002310-appb-img-000133
Figure PCTKR2022002310-appb-img-000133
수득률: 25 %; 1H-NMR (400MHz, CDCl3) δ 2.19 (3H, s), 3.47 (3H, s), 5.92 (2H, s), 6.47 (1H, s), 6.67 (1H, s), 7.38-7.42 (2H, m), 7.51-7.55 (2H, t), 7.68-7.70 (2H, m), 7.92 (1H, s)Yield: 25%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.19 (3H, s), 3.47 (3H, s), 5.92 (2H, s), 6.47 (1H, s), 6.67 (1H, s), 7.38-7.42 ( 2H, m), 7.51-7.55 (2H, t), 7.68-7.70 (2H, m), 7.92 (1H, s)
실시예 21: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one}의 제조Example 21: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H- Purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin- Preparation of 8-one}
Figure PCTKR2022002310-appb-img-000134
Figure PCTKR2022002310-appb-img-000134
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 2.53 (3H, s), 3.51 (3H, s), 7.09 (1H, s), 7.45-7.55 (1H, m), 7.57-7.63 (2H, m), 7.72-7.80 (2H, m), 8.09 (1H, s), 9.05 (1H, s)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.53 (3H, s), 3.51 (3H, s), 7.09 (1H, s), 7.45-7.55 (1H, m), 7.57-7.63 (2H, m), 7.72-7.80 (2H, m), 8.09 (1H, s), 9.05 (1H, s)
실시예 22: 2-((4,7-디메틸-2-옥소-2H-크로멘-6-일)아미노)-7-메틸-9-페닐-7,9-디하이드로-8H-푸린-8-온 {2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one}의 제조Example 22: 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purine-8 -one {2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one} manufacture of
Figure PCTKR2022002310-appb-img-000135
Figure PCTKR2022002310-appb-img-000135
수득률: 32 %; 1H-NMR (400MHz, CDCl3) δ 2.13 (3H, s), 2.40 (3H, s), 3.50 (3H, s), 6.20 (1H, s), 6.79 (1H, s), 7.16 (1H, s), 7.42-7.50 (1H, m), 7.52-7.56 (2H, m), 7.62-7.68 (2H, m), 7.99 (1H, s), 8.31 (1H, s)Yield: 32%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.13 (3H, s), 2.40 (3H, s), 3.50 (3H, s), 6.20 (1H, s), 6.79 (1H, s), 7.16 (1H, s), 7.42-7.50 (1H, m), 7.52-7.56 (2H, m), 7.62-7.68 (2H, m), 7.99 (1H, s), 8.31 (1H, s)
실시예 23: 7-메틸-2-((4-메틸-6-(트리플루오로메틸)피리딘-3-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one}의 제조Example 23: 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purine-8- Preparation of one {7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000136
Figure PCTKR2022002310-appb-img-000136
수득률: 45 %; 1H-NMR (400MHz, CDCl3) δ 2.37 (3H, s), 3.51 (3H, s), 6.78 (1H, s), 7.44-7.48 (2H, m), 7.54-7.58 (2H, m), 7.64-7.66 (2H, m), 8.01 (1H, s), 9.54 (1H, s)Yield: 45%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.37 (3H, s), 3.51 (3H, s), 6.78 (1H, s), 7.44-7.48 (2H, m), 7.54-7.58 (2H, m), 7.64-7.66 (2H, m), 8.01 (1H, s), 9.54 (1H, s)
실시예 24: 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 24: 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-thio Pyran-4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin) Preparation of -3-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000137
Figure PCTKR2022002310-appb-img-000137
수득률: 25 %; 1H-NMR (400MHz, CDCl3) δ 2.11 (2H, m), 2.39 (3H, s), 2.78 (3H, q), 2.89 (3H, q), 3.41 (3H, s), 3.98 (3H, s), 4.30 (1H, m), 6.57 (1H, s), 7.36 (1H, s), 7.86 (1H, s), 7.93 (2H, d), 9.07 (1H, s)Yield: 25%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.11 (2H, m), 2.39 (3H, s), 2.78 (3H, q), 2.89 (3H, q), 3.41 (3H, s), 3.98 (3H, s), 4.30 (1H, m), 6.57 (1H, s), 7.36 (1H, s), 7.86 (1H, s), 7.93 (2H, d), 9.07 (1H, s)
실시예 25: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(스피로[3.3]헵탄-2-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 25: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7,9-di Hydro-8H-purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7 Preparation of ,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000138
Figure PCTKR2022002310-appb-img-000138
수득률: 39 %; 1H-NMR (400MHz, CDCl3) δ 1.83-2.41 (8H, m), 2.46 (3H, s), 2.81 (3H, s), 2.97-3.03 (2H, m), 3.38 (3H, s), 4.71-4.80 (1H, m), 6.84-8.59 (4H, m)Yield: 39%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.83-2.41 (8H, m), 2.46 (3H, s), 2.81 (3H, s), 2.97-3.03 (2H, m), 3.38 (3H, s), 4.71-4.80 (1H, m), 6.84-8.59 (4H, m)
실시예 26: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(스피로[3.3]헵탄-2-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 26: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[3.3]heptan-2-yl) -7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro [3.3] Preparation of heptan-2-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000139
Figure PCTKR2022002310-appb-img-000139
수득률: 9 %; 1H-NMR (400MHz, CDCl3) δ 1.85-2.46 (8H, m), 2.57 (3H, s), 3.06-3.12 (2H, m), 3.41 (3H, s), 4.79-4.88 (1H, m), 7.07-8.97 (4H, m)Yield: 9%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.85-2.46 (8H, m), 2.57 (3H, s), 3.06-3.12 (2H, m), 3.41 (3H, s), 4.79-4.88 (1H, m) ), 7.07-8.97 (4H, m)
실시예 27: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-9-(3-메톡시사이클로부틸)-7-메틸-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one}의 제조Example 27: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H -Purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin- Preparation of 8-one}
Figure PCTKR2022002310-appb-img-000140
Figure PCTKR2022002310-appb-img-000140
수득률: 17 %; 1H-NMR (400MHz, CDCl3) δ 2.48 (3H, s), 2.68-2.75 (2H, m), 2.80 (3H, s), 3.08-3.15 (2H, m), 3.33 (3H, s), 3.39 (3H, s), 3.75-3.82 (1H,m), 4.48-4.57 (1H, m), 6.93-8.70 (4H, m)Yield: 17%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.48 (3H, s), 2.68-2.75 (2H, m), 2.80 (3H, s), 3.08-3.15 (2H, m), 3.33 (3H, s), 3.39 (3H, s), 3.75-3.82 (1H,m), 4.48-4.57 (1H, m), 6.93-8.70 (4H, m)
실시예 28: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-옥사스피로[3.3]헵탄-6-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 28: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7, 9-dihydro-8H-purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6 Preparation of -yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000141
Figure PCTKR2022002310-appb-img-000141
수득률: 31 %; 1H-NMR (400MHz, CDCl3) δ 2.45 (3H, s), 2.64-2.70 (2H, m), 2.81 (3H, s), 3.16-3.22 (2H, m), 3.38 (3H, s), 4.66 (2H, s), 4.71-4.80 (3H, m), 6.77-8.48 (4H, m)Yield: 31%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.45 (3H, s), 2.64-2.70 (2H, m), 2.81 (3H, s), 3.16-3.22 (2H, m), 3.38 (3H, s), 4.66 (2H, s), 4.71-4.80 (3H, m), 6.77-8.48 (4H, m)
실시예 29: 7-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 29: 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5 ] Nonan-7-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl) Preparation of pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000142
Figure PCTKR2022002310-appb-img-000142
수득률: 10 %; 1H-NMR (400MHz, CDCl3) δ 1.56 (2H, m), 1.73 (2H, d), 2.29 (4H, d), 2.33 (3H, s), 3.38 (3H, s), 3.95 (3H, s), 4.23 (1H, m), 4.37 (2H, s), 4.51 (2H, s), 6.53 (1H, s), 7.33 (1H, s), 7.84 (1H, s), 7.89 (2H, d), 8.95 (1H, s)Yield: 10%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.56 (2H, m), 1.73 (2H, d), 2.29 (4H, d), 2.33 (3H, s), 3.38 (3H, s), 3.95 (3H, s), 4.23 (1H, m), 4.37 (2H, s), 4.51 (2H, s), 6.53 (1H, s), 7.33 (1H, s), 7.84 (1H, s), 7.89 (2H, d), 8.95 (1H, s)
실시예 30: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione}의 제조Example 30: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purine-8-thione {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-( Preparation of tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione}
Figure PCTKR2022002310-appb-img-000143
Figure PCTKR2022002310-appb-img-000143
수득률: 5 %; 1H-NMR (400MHz, CDCl3) δ 1.82 (2H, dd), 2.74 (3H, s), 2.79 (2H, m), 2.87 (2H, dq), 3.54 (3H, t), 4.16 (2H, dd), 4.41 (1H, m), 7.03-8.64 (4H, m)Yield: 5%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.82 (2H, dd), 2.74 (3H, s), 2.79 (2H, m), 2.87 (2H, dq), 3.54 (3H, t), 4.16 (2H, dd), 4.41 (1H, m), 7.03-8.64 (4H, m)
실시예 31: 4-메틸-5-((7-메틸-9-(테트라하이드로-2H-피란-4-일)-8-티옥소-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 31: 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl )amino)picolinamide {4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl Preparation of )amino)picolinamide}
Figure PCTKR2022002310-appb-img-000144
Figure PCTKR2022002310-appb-img-000144
2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온과 실시예 14의 단계 1을 통해 얻어진 5-아미노-4-메틸피콜린아미드의 커플링반응을 수행하여 목적 화합물을 수득하였다(수득률: 18 %). 1H-NMR (400MHz, CDCl3) δ 1.84 (2H, dd), 2.44 (3H, s), 2.80 (3H, s), 2.88 (2H, dq), 3.57 (2H, t), 4.20 (2H, dd), 4.44 (1H, m), 5.51 (1H, br), 7.00-9.56 (5H, m)2-Chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione and 5-amino obtained through step 1 of Example 14 A coupling reaction of -4-methylpicolinamide was performed to obtain the target compound (yield: 18%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.84 (2H, dd), 2.44 (3H, s), 2.80 (3H, s), 2.88 (2H, dq), 3.57 (2H, t), 4.20 (2H, dd), 4.44 (1H, m), 5.51 (1H, br), 7.00-9.56 (5H, m)
실시예 32: 7-메틸-2-((4-메틸-6-((1-메틸-1H-피라졸-4-일)아미노)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 32: 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4- Preparation of yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000145
Figure PCTKR2022002310-appb-img-000145
Figure PCTKR2022002310-appb-img-000146
Figure PCTKR2022002310-appb-img-000146
단계 1: 4-메틸-N-(1-메틸-1H-피라졸-4-일)-5-니트로피리딘-2-아민 {4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridin-2-amine}의 제조Step 1: 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridin-2-amine {4-methyl-N-(1-methyl-1H-pyrazol-4- Preparation of yl)-5-nitropyridin-2-amine}
2-브로모-4-메틸-5-니트로피리딘 100 mg, 1-메틸-1H-피라졸-4-아민 53 mg, 세슘카보네이트 300 mg, 팔라듐(II)아세테이트 18 mg 및 쟌트포스 46 mg을 다이옥산 2 mL에 넣은 후, 마이크로웨이브를 사용하여 130 ℃에서 30 분 동안 반응하였다. 반응 종결 후, 셀라이트 여과하고 농축하였다. MPLC로 정제하여 목적 화합물을 수득하였다(수득률: 54 %). 100 mg of 2-bromo-4-methyl-5-nitropyridine, 53 mg of 1-methyl-1H-pyrazol-4-amine, 300 mg of cesium carbonate, 18 mg of palladium (II) acetate and 46 mg of xanthos are dioxane After adding to 2 mL, the reaction was conducted at 130° C. for 30 minutes using a microwave. After completion of the reaction, it was filtered through Celite and concentrated. Purification by MPLC gave the target compound (yield: 54%).
단계 2: 4-메틸-N-(1-메틸-1H-피라졸-4-일)피리딘-2,5-디아민 {4-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2,5-diamine}의 제조Step 2: 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyridine-2,5-diamine {4-methyl-N-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-2,5-diamine}
단계 1에서 수득한 4-메틸-N-(1-메틸-1H-피라졸-4-일)-5-니트로피리딘-2-아민 57 mg, 아연 80 mg 및 암모늄클로라이드 65 mg을 에탄올 2 mL에 투입한 후, 90 ℃에서 6 시간 동안 반응하였다. 반응 종료 후, 셀라이트 여과하고 농축한 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다. Mass 확인 후 NMR 분석 없이 다음 단계의 반응을 진행하였다(수득률: 36 %).57 mg of 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridin-2-amine obtained in step 1, 80 mg of zinc and 65 mg of ammonium chloride were dissolved in 2 mL of ethanol After the addition, the reaction was carried out at 90 °C for 6 hours. After completion of the reaction, the residue filtered through Celite and concentrated was purified by Prep-HPLC to obtain the target compound. After confirming the mass, the reaction of the next step was carried out without NMR analysis (yield: 36%).
단계 3: 7-메틸-2-((4-메틸-6-((1-메틸-1H-피라졸-4-일)아미노)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Step 3: 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H -Pyran-4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl) Preparation of )amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
실시예 1과 실질적으로 동일한 방법으로, 단계 2에서 수득한 4-메틸-N-(1-메틸-1H-피라졸-4-일)피리딘-2,5-디아민과 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온의 반응을 통해 목적 화합물을 얻었다(수득률: 18 %). 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.22 (3H, s), 2.75 (2H, m), 3.39 (3H, s), 3.54 (2H, t), 3.95 (3H, s), 4.13 (2H, dd), 4.51 (1H, m), 5.89-8.30 (7H, m)In substantially the same manner as in Example 1, 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyridine-2,5-diamine and 2-chloro-7-methyl obtained in step 2 The target compound was obtained through the reaction of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (yield: 18%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.22 (3H, s), 2.75 (2H, m), 3.39 (3H, s), 3.54 (2H, t), 3.95 (3H, s), 4.13 (2H, dd), 4.51 (1H, m), 5.89-8.30 (7H, m)
실시예 33: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피리딘-2-일 메탄설포네이트 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)pyridin-2-yl methanesulfonate}의 제조Example 33: 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)pyridin-2-yl methanesulfonate {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin) Preparation of -2-yl)amino)pyridin-2-yl methanesulfonate}
Figure PCTKR2022002310-appb-img-000147
Figure PCTKR2022002310-appb-img-000147
Figure PCTKR2022002310-appb-img-000148
Figure PCTKR2022002310-appb-img-000148
단계 1: 4-메틸-5-니트로피리딘-2-일 메탄설포네이트 (4-methyl-5-nitropyridin-2-yl methanesulfonate)의 제조Step 1: Preparation of 4-methyl-5-nitropyridin-2-yl methanesulfonate (4-methyl-5-nitropyridin-2-yl methanesulfonate)
4-메틸-5-니트로피리딘-2-올 100 mg을 디클로로메탄 3 mL에 넣고, 0 ℃에서 10 분 동안 교반하였다. 트리에틸아민 0.178 mL 및 메탄설포닐클로라이드 88 mg을 순차적으로 넣고, 30 분 동안 냉각 교반한 후, 상온에서 2 시간 더 교반하였다. 디클로로메탄 10 mL와 정제수 10 mL을 더 넣고 디클로로메탄 층을 분리하여 마그네슘설페이트 처리한 후, 여과하고 농축한 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 30 %). 1H-NMR (400MHz, CDCl3) δ 2.71 (3H, s), 3.56 (3H, s), 7.09 (1H, s), 8.99 (1H, s)) 100 mg of 4-methyl-5-nitropyridin-2-ol was added to 3 mL of dichloromethane, and the mixture was stirred at 0° C. for 10 minutes. 0.178 mL of triethylamine and 88 mg of methanesulfonyl chloride were sequentially added, followed by cooling and stirring for 30 minutes, followed by stirring at room temperature for 2 hours. 10 mL of dichloromethane and 10 mL of purified water were added, and the dichloromethane layer was separated, treated with magnesium sulfate, filtered, and the concentrated residue was purified by Prep-HPLC to obtain the target compound (yield: 30%). 1 H-NMR (400 MHz, CDCl 3 ) δ 2.71 (3H, s), 3.56 (3H, s), 7.09 (1H, s), 8.99 (1H, s))
단계 2: 5-아미노-4-메틸피리딘-2-일 메탄설포네이트 (5-amino-4-methylpyridin-2-yl methanesulfonate)의 제조Step 2: Preparation of 5-amino-4-methylpyridin-2-yl methanesulfonate (5-amino-4-methylpyridin-2-yl methanesulfonate)
수득한 4-메틸-5-니트로피리딘-2-일 메탄설포네이트 44 mg, 아연 62 mg 및 암모늄클로라이드 51 mg을 에탄올 2 mL에 투입하였다. 90 ℃에서 6 시간 동안 환류 교반한 후, 에틸아세테이트 10 mL와 정제수 10 mL를 더 넣고, 에틸아세테이트 층을 분리하였다. 얻어진 에틸아세테이트 층을 농축한 후, Prep-HPLC로 정제하여 목적 화합물을 수득하였다. Mass 확인 후 NMR 분석 없이 다음 단계의 반응을 진행하였다(수득률: 26 %).44 mg of the obtained 4-methyl-5-nitropyridin-2-yl methanesulfonate, 62 mg of zinc and 51 mg of ammonium chloride were added to 2 mL of ethanol. After stirring under reflux at 90° C. for 6 hours, 10 mL of ethyl acetate and 10 mL of purified water were further added, and the ethyl acetate layer was separated. After concentrating the obtained ethyl acetate layer, it was purified by Prep-HPLC to obtain the target compound. After confirming the mass, the reaction of the next step was carried out without NMR analysis (yield: 26%).
단계 3: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피리딘-2-일 메탄설포네이트 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)pyridin-2-yl methanesulfonate}의 제조Step 3: 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )pyridin-2-yl methanesulfonate {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- Preparation of 2-yl)amino)pyridin-2-yl methanesulfonate}
실시예 1과 실질적으로 동일한 방법으로, 상기 제조예 1에서 제조한 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온과 상기 단계 2에서 얻은 5-아미노-4-메틸피리딘-2-일 메탄설포네이트를 반응하여 목적 화합물을 얻었다(수득률: 21 %). 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.39 (3H, s), 2.73 (2H, m), 3.41 (3H, s), 3.47 (3H, s), 3.53 (2H, t), 4.13 (2H, dd), 4.53 (1H, m), 6.59-9.06 (4H, m)In substantially the same manner as in Example 1, 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine prepared in Preparation Example 1 -8-one and 5-amino-4-methylpyridin-2-yl methanesulfonate obtained in step 2 were reacted to obtain the target compound (yield: 21%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.39 (3H, s), 2.73 (2H, m), 3.41 (3H, s), 3.47 (3H, s), 3.53 (2H, t), 4.13 (2H, dd), 4.53 (1H, m), 6.59-9.06 (4H, m)
실시예 34: 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 34: 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000149
Figure PCTKR2022002310-appb-img-000149
Figure PCTKR2022002310-appb-img-000150
Figure PCTKR2022002310-appb-img-000150
단계 1: 6-(푸란-3-일)-4-메틸피리딘-3-아민 {6-(furan-3-yl)-4-methylpyridin-3-amine}의 제조Step 1: Preparation of 6-(furan-3-yl)-4-methylpyridin-3-amine {6-(furan-3-yl)-4-methylpyridin-3-amine}
6-브로모-4-메틸피리딘-3-아민 200 mg, 푸란-3-일 보론산 174 mg, Pd(dppf)Cl2 39 mg 및 2M-탄산칼륨 수용액 1 mL을 다이옥산 3 mL에 넣고, 130 ℃에서 16 시간 동안 환류 교반하였다. 반응물을 셀라이트 여과하고 농축한 잔사물을 Prep-HPLC로 정제하여 6-(푸란-3-일)-4-메틸피리딘-3-아민을 수득하였다(수득률: 75%). Mass 확인 후, NMR 분석 없이 다음 단계의 반응을 진행하였다.200 mg of 6-bromo-4-methylpyridin-3-amine, 174 mg of furan-3-yl boronic acid, 39 mg of Pd(dppf)Cl 2 and 1 mL of 2M-potassium carbonate aqueous solution were placed in 3 mL of dioxane, 130 The mixture was stirred under reflux at ℃ for 16 hours. The reaction was filtered through Celite, and the concentrated residue was purified by Prep-HPLC to obtain 6-(furan-3-yl)-4-methylpyridin-3-amine (yield: 75%). After confirming the mass, the reaction of the next step was performed without NMR analysis.
단계 2: 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Step 2: 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran Preparation of -4-yl)-7,9-dihydro-8H-purin-8-one}
실시예 1과 실질적으로 동일한 방법으로, 상기 제조예 1에서 제조한 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온과 단계 1에서 얻은 6-(푸란-3-일)-4-메틸피리딘-3-아민을 반응하여 목적 화합물을 얻었다(수득률: 11 %).In substantially the same manner as in Example 1, 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine prepared in Preparation Example 1 The target compound was obtained by reacting -8-one with 6-(furan-3-yl)-4-methylpyridin-3-amine obtained in step 1 (yield: 11 %).
1H-NMR (400MHz, CDCl3) δ 1.72 (2H, d), 2.37 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (3H, dd), 4.50-4.57 (1H, m), 6.60-9.17 (7H, m), 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, d), 2.37 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (3H, dd), 4.50-4.57 (1H, m), 6.60-9.17 (7H, m),
<실시예 35 내지 실시예 59><Examples 35 to 59>
실시예 35 내지 실시예 59에서는 실시예 34와 실질적으로 동일한 방법으로 적절한 중간체, 아민 유도체 및 보론산 유도체를 사용하여 제조하였다.Examples 35 to 59 were prepared in substantially the same manner as in Example 34, using appropriate intermediates, amine derivatives and boronic acid derivatives.
실시예 35: 7-메틸-2-((4-메틸-6-(3-메틸티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 35: 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000151
Figure PCTKR2022002310-appb-img-000151
수득률: 21 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, d), 2.40 (3H, s), 2.52 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.51-4.57 (1H, m), 6.61-9.24 (6H, m)Yield: 21%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, d), 2.40 (3H, s), 2.52 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.51-4.57 (1H, m), 6.61-9.24 (6H, m)
실시예 36: 7-메틸-2-((4-메틸-6-(5-메틸티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 36: 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000152
Figure PCTKR2022002310-appb-img-000152
수득률: 21 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, m), 2.30 (3H, s), 2.38 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.12 (2H, dd), 4.50-4.56 (1H, m), 6.59-9.18 (6H, s)Yield: 21%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, m), 2.30 (3H, s), 2.38 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.12 (2H, dd), 4.50-4.56 (1H, m), 6.59-9.18 (6H, s)
실시예 37: 7-메틸-2-((4-메틸-6-(티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 37: 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000153
Figure PCTKR2022002310-appb-img-000153
수득률: 24 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, m), 2.39 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.51-4.57 (1H, m), 6.61-9.21 (7H, m)Yield: 24%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, m), 2.39 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.51-4.57 (1H, m), 6.61-9.21 (7H, m)
실시예 38: 2-((6-(푸란-3-일)-2-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 38: 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one {2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000154
Figure PCTKR2022002310-appb-img-000154
수득률: 15 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, d), 2.63 (3H, s), 2.72-2.82 (2H, m), 3.41 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.58 (1H, m), 6.76-8.51 (7H, m)Yield: 15%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, d), 2.63 (3H, s), 2.72-2.82 (2H, m), 3.41 (3H, s), 3.55 (2H, t), 4.14 ( 2H, dd), 4.51-4.58 (1H, m), 6.76-8.51 (7H, m)
실시예 39: 7-메틸-2-((4-메틸-6-(티오펜-3-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 39: 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000155
Figure PCTKR2022002310-appb-img-000155
수득률: 9 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, d), 2.39 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.50-4.57 (1H, m), 6.62-9.22 (7H, m)Yield: 9%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, d), 2.39 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.50-4.57 (1H, m), 6.62-9.22 (7H, m)
실시예 40: 7-메틸-2-((4-메틸-6-(5-메틸푸란-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 40: 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000156
Figure PCTKR2022002310-appb-img-000156
수득률: 11 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, d), 2.37 (3H, s), 2.40 (3H, s), 2.74 (2H, m), 3.39 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.50-4.57 (1H, m), 6.10-9.20 (6H, m)Yield: 11%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, d), 2.37 (3H, s), 2.40 (3H, s), 2.74 (2H, m), 3.39 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.50-4.57 (1H, m), 6.10-9.20 (6H, m)
실시예 41: 2-((6-(푸란-2-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 41: 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one {2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000157
Figure PCTKR2022002310-appb-img-000157
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, d), 2.39 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.51-4.57 (1H, m), 6.52-9.24 (7H, m)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, d), 2.39 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.51-4.57 (1H, m), 6.52-9.24 (7H, m)
실시예 42: 7-메틸-2-((4-메틸-6-(2-메틸옥사졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 42: 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000158
Figure PCTKR2022002310-appb-img-000158
수득률: 22 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.40 (3H, s), 2.56 (3H, s), 2.74 (2H, m), 3.41 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.50-4.58 (1H, m), 6.75-9.31 (5H, m)Yield: 22%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.40 (3H, s), 2.56 (3H, s), 2.74 (2H, m), 3.41 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.50-4.58 (1H, m), 6.75-9.31 (5H, m)
실시예 43: 7-메틸-2-((4-메틸-6-(2-메틸티아졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 43: 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000159
Figure PCTKR2022002310-appb-img-000159
수득률: 29 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.39 (3H, s), 2.71-2.81 (5H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (1H, dd), 4.38-4.46 (1H, m), 6.67-9.25 (5H, m)Yield: 29%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.39 (3H, s), 2.71-2.81 (5H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 ( 1H, dd), 4.38-4.46 (1H, m), 6.67-9.25 (5H, m)
실시예 44: 7-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 44: 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino) Preparation of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000160
Figure PCTKR2022002310-appb-img-000160
수득률: 21 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.42 (3H, s), 2.54 (3H, s), 2.76 (2H, m), 3.41 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.68-9.40 (5H, m)Yield: 21%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.42 (3H, s), 2.54 (3H, s), 2.76 (2H, m), 3.41 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.68-9.40 (5H, m)
실시예 45: 7-메틸-2-((4-메틸-6-(옥사졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 45: 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000161
Figure PCTKR2022002310-appb-img-000161
수득률: 32 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.42 (3H, s), 2.76 (2H, m), 3.41 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.69-9.39 (6H, m)Yield: 32%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.42 (3H, s), 2.76 (2H, m), 3.41 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.69-9.39 (6H, m)
실시예 46: 7-메틸-2-((4-메틸-6-(옥사졸-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 46: 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000162
Figure PCTKR2022002310-appb-img-000162
수득률: 34 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.44 (3H, s), 2.76 (2H, m), 3.42 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.75-9.55 (6H, s)Yield: 34%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.44 (3H, s), 2.76 (2H, m), 3.42 (3H, s), 3.55 (2H, t), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.75-9.55 (6H, s)
실시예 47: 2-((6-(벤조[d][1,3]디옥솔-5-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 47: 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one {2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin Preparation of -3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000163
Figure PCTKR2022002310-appb-img-000163
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.39 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.50-4.58 (1H, m), 6.01 (2H, s), 6.64-9.21 (7H, m)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.39 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.50-4.58 (1H, m), 6.01 (2H, s), 6.64-9.21 (7H, m)
실시예 48: 7-메틸-2-((4-메틸-6-(5-메틸이소옥사졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 48: 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000164
Figure PCTKR2022002310-appb-img-000164
수득률: 18 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.40 (3H, s), 2.77 (3H, s), 3.41 (3H, d), 3.54 (2H, t), 4.13 (2H, dd), 4.54 (1H, m), 6.61-9.27 (5H, m)Yield: 18%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.40 (3H, s), 2.77 (3H, s), 3.41 (3H, d), 3.54 (2H, t), 4.13 (2H, dd), 4.54 (1H, m), 6.61-9.27 (5H, m)
실시예 49: 7-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 49: 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000165
Figure PCTKR2022002310-appb-img-000165
수득률: 14 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.36 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 3.95 (3H, s), 4.13 (2H, dd), 4.54 (1H, m), 6.64-9.11 (6H, m)Yield: 14%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.36 (3H, s), 2.76 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 3.95 (3H, s), 4.13 (2H, dd), 4.54 (1H, m), 6.64-9.11 (6H, m)
실시예 50: 7-메틸-2-((4-메틸-6-(1-메틸-1H-피롤-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 50: 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3 Preparation of -yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000166
Figure PCTKR2022002310-appb-img-000166
수득률: 61 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.35 (3H, s), 2.75 (2H, m), 3.39 (3H, s), 3.53 (2H, t), 3.98 (3H, s), 4.12 (2H, dd), 4.53 (1H, m), 6.16-9.13 (7H, m)Yield: 61%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.35 (3H, s), 2.75 (2H, m), 3.39 (3H, s), 3.53 (2H, t), 3.98 (3H, s), 4.12 (2H, dd), 4.53 (1H, m), 6.16-9.13 (7H, m)
실시예 51: 2-((6-(2,5-디하이드로푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 51: 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one {2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7 Preparation of -methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000167
Figure PCTKR2022002310-appb-img-000167
수득률: 6 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.36 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.54 (1H, m), 4.90 (2H, m), 5.11 (2H, m), 6.48-9.25 (5H, m)Yield: 6%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.36 (3H, s), 2.75 (2H, m), 3.40 (3H, s), 3.54 (2H, t), 4.13 (2H, dd), 4.54 (1H, m), 4.90 (2H, m), 5.11 (2H, m), 6.48-9.25 (5H, m)
실시예 52: 2-((6-(4,5-디하이드로푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 52: 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one {2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7 Preparation of -methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000168
Figure PCTKR2022002310-appb-img-000168
수득률: 5 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.36 (3H, s), 2.74 (2H, m), 3.05 (3H, s), 3.39 (3H, s), 3.53 (2H, dd), 4.12 (2H, dd), 4.49-4.59 (3H, m), 6.51-9.25 (5H, m)Yield: 5%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.36 (3H, s), 2.74 (2H, m), 3.05 (3H, s), 3.39 (3H, s), 3.53 (2H, dd), 4.12 (2H, dd), 4.49-4.59 (3H, m), 6.51-9.25 (5H, m)
실시예 53: 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 53: 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5 ] Nonan-7-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000169
Figure PCTKR2022002310-appb-img-000169
수득률: 6 %; 1H-NMR (400MHz, CDCl3) δ 1.58 (2H, m), 1.76 (2H, d), 2.30 (4H, d), 2.36 (3H, s), 3.40 (3H, s), 3.97 (3H, s), 4.26 (1H, m), 4.39 (2H, s), 4.53 (2H, s), 6.55 (1H, s), 7.35 (1H, s), 7.86 (1H, s), 7.91 (2H, d), 8.97 (1H, s)Yield: 6%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.58 (2H, m), 1.76 (2H, d), 2.30 (4H, d), 2.36 (3H, s), 3.40 (3H, s), 3.97 (3H, s), 4.26 (1H, m), 4.39 (2H, s), 4.53 (2H, s), 6.55 (1H, s), 7.35 (1H, s), 7.86 (1H, s), 7.91 (2H, d) ), 8.97 (1H, s)
실시예 54: 7-메틸-2-((4-메틸-6-(티오펜-2-일)피리딘-3-일)아미노)-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 54: 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7,9- Dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7 Preparation of ,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000170
Figure PCTKR2022002310-appb-img-000170
수득률: 47 %; 1H-NMR (400MHz, CDCl3) δ 2.36 (3H, s), 2.51 (4H, br), 2.71 (2H, t), 3.40 (3H, s), 3.57 (4H, t), 4.01 (2H, t), 6.72 (1H, s), 7.09 (1H, t), 7.33 (1H, d), 7.49 (1H, d), 7.50 (1H, s), 7.84 (1H, s), 9.17 (1H, s)Yield: 47%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.36 (3H, s), 2.51 (4H, br), 2.71 (2H, t), 3.40 (3H, s), 3.57 (4H, t), 4.01 (2H, t), 6.72 (1H, s), 7.09 (1H, t), 7.33 (1H, d), 7.49 (1H, d), 7.50 (1H, s), 7.84 (1H, s), 9.17 (1H, s)
실시예 55: 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-morpholino-7,9-dihydro-8H-purin-8-one}의 제조Example 55: 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-morpholino-7,9 -dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9- Preparation of morpholino-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000171
Figure PCTKR2022002310-appb-img-000171
수득률: 10 %; 1H-NMR (400MHz, CDCl3) δ 2.35 (3H, s), 3.38 (3H, s), 3.52 (4H, m), 3.93 (4H, t), 3.96 (3H, s), 6.65 (1H, s), 7.33 (1H, s) 7.85 (1H, s), 7.91 (2H, d), 9.06 (1H, s)Yield: 10%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.35 (3H, s), 3.38 (3H, s), 3.52 (4H, m), 3.93 (4H, t), 3.96 (3H, s), 6.65 (1H, s), 7.33 (1H, s) 7.85 (1H, s), 7.91 (2H, d), 9.06 (1H, s)
실시예 56: 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 56: 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(spiro[2.5]octane- 6-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3) Preparation of -yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000172
Figure PCTKR2022002310-appb-img-000172
수득률: 11 %; 1H-NMR (400MHz, CDCl3) δ 0.34 (4H, s), 0.97 (2H, d), 1.73 (2H, d), 1.93 (2H, t), 2.36 (3H, s), 2.54 (2H, q), 3.39 (3H, s), 3.97 (3H, s), 4.33 (1H, t), 6.57 (1H, s), 7.34 (1H, s), 7.84 (1H, s), 7.89 (1H, s), 7.92 (1H, s), 9.05 (1H, s)Yield: 11%; 1 H-NMR (400 MHz, CDCl 3 ) δ 0.34 (4H, s), 0.97 (2H, d), 1.73 (2H, d), 1.93 (2H, t), 2.36 (3H, s), 2.54 (2H, q), 3.39 (3H, s), 3.97 (3H, s), 4.33 (1H, t), 6.57 (1H, s), 7.34 (1H, s), 7.84 (1H, s), 7.89 (1H, s) ), 7.92 (1H, s), 9.05 (1H, s)
실시예 57: 7-에틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 57: 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one {7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000173
Figure PCTKR2022002310-appb-img-000173
수득률: 50 %; 1H-NMR (400MHz, CDCl3) δ 1.36 (3H, t), 1.73 (2H, dd), 2.37 (3H, s), 2.76 (2H, m), 3.54 (2H, t), 3.89 (2H, q), 3.95 (3H, s), 4.13 (2H, dd), 4.54 (1H, m), 6.67-9.06 (6H, m)Yield: 50%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36 (3H, t), 1.73 (2H, dd), 2.37 (3H, s), 2.76 (2H, m), 3.54 (2H, t), 3.89 (2H, q), 3.95 (3H, s), 4.13 (2H, dd), 4.54 (1H, m), 6.67-9.06 (6H, m)
실시예 58: 7-에틸-2-((4-메틸-6-(옥사졸-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 58: 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one {7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000174
Figure PCTKR2022002310-appb-img-000174
수득률: 80 %; 1H-NMR (400MHz, CDCl3) δ 1.38 (3H, t), 1.74 (2H, dd), 2.44 (3H, s), 2.76 (2H, m), 3.55 (2H, t), 3.92 (2H, q), 3.95 (3H, s), 4.14 (2H, dd), 4.56 (1H, m), 6.82-9.55 (6H, m)Yield: 80%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.38 (3H, t), 1.74 (2H, dd), 2.44 (3H, s), 2.76 (2H, m), 3.55 (2H, t), 3.92 (2H, q), 3.95 (3H, s), 4.14 (2H, dd), 4.56 (1H, m), 6.82-9.55 (6H, m)
실시예 59: 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 59: 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000175
Figure PCTKR2022002310-appb-img-000175
수득률: 8 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, dd), 2.36 (3H, s), 2.75 (2H, m), 3.39 (3H, s), 3.53 (2H, t), 3.95 (3H, s), 4.12 (2H, dd), 4.48-4.57 (1H, m), 6.63-9.08 (6H, m)Yield: 8%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, dd), 2.36 (3H, s), 2.75 (2H, m), 3.39 (3H, s), 3.53 (2H, t), 3.95 (3H, s), 4.12 (2H, dd), 4.48-4.57 (1H, m), 6.63-9.08 (6H, m)
실시예 60: 2-((5-플루오로-2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 60: 2-((5-Fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H- Pyran-4-yl)-7,9-dihydro-8H-purin-8-one {2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl) Preparation of )amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000176
Figure PCTKR2022002310-appb-img-000176
단계 1: 5-플루오로-2-메틸-4-(1-메틸-1H-이미다졸-4-일)아닐린 {5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)aniline}의 제조Step 1: 5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)aniline {5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4) Preparation of -yl)aniline}
Figure PCTKR2022002310-appb-img-000177
Figure PCTKR2022002310-appb-img-000177
4-브로모-5-플루오로-2-메틸아닐린 80 mg, 1-메틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-이미다졸 59 mg, 2M-포타슘카보네이트 0.5 ml 및 Pd(dppf)Cl2 29 mg을 다이옥산 2 mL에 투입한 후 130 ℃에서 16 시간 동안 환류 교반하였다. 반응물을 셀라이트 여과하고 농축한 잔사물을 Prep-HPLC로 정제하여 표제 화합물을 수득하였다(수율: 58 %). 1H-NMR (400MHz, CDCl3) δ 2.15 (3H, s), 3.67 (2H, br), 3.93 (3H, s), 6.43 (1H, d), 7.18 (1H, d), 7.63 (1H, d), 7.74 (1H, s)4-bromo-5-fluoro-2-methylaniline 80 mg, 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 59 mg of -1H-imidazole, 0.5 ml of 2M-potassium carbonate, and 29 mg of Pd(dppf)Cl 2 were added to 2 mL of dioxane, followed by stirring under reflux at 130° C. for 16 hours. The reaction was filtered through Celite, and the concentrated residue was purified by Prep-HPLC to obtain the title compound (Yield: 58%). 1 H-NMR (400 MHz, CDCl 3 ) δ 2.15 (3H, s), 3.67 (2H, br), 3.93 (3H, s), 6.43 (1H, d), 7.18 (1H, d), 7.63 (1H, d), 7.74 (1H, s)
단계 2: 2-((5-플루오로-2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Step 2: 2-((5-Fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one {2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl) Preparation of amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
실시예 1과 실질적으로 동일한 방법으로, 상기 제조예 1에서 제조한 2-클로로-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온과 상기 단계 1에서 얻은 5-플루오로-2-메틸-4-(1-메틸-1H-이미다졸-4-일)아닐린을 반응하여 목적 화합물을 얻었다(수득률: 64 %). 1H-NMR (400MHz, CDCl3) δ 1.74 (2H, dd), 2.35 (3H, s), 2.73-2.84 (2H, m), 3.40 (3H, s), 3.55 (2H, t), 3.95 (3H, s), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.81-8.22 (6H, m)In substantially the same manner as in Example 1, 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine prepared in Preparation Example 1 -8-one was reacted with 5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)aniline obtained in step 1 to obtain the target compound (yield: 64%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, dd), 2.35 (3H, s), 2.73-2.84 (2H, m), 3.40 (3H, s), 3.55 (2H, t), 3.95 ( 3H, s), 4.14 (2H, dd), 4.51-4.59 (1H, m), 6.81-8.22 (6H, m)
실시예 61: 2-((5-플루오로-2-메틸-4-(2-메틸옥사졸-5-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 61: 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one {2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl Preparation of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000178
Figure PCTKR2022002310-appb-img-000178
실시예 60과 실질적으로 동일한 방법으로 적절한 아닐린 유도체와 보론산 유도체를 사용하여 제조하였다(수득률: 4 %). 1H-NMR (400MHz, CDCl3) δ 1.74 (2H, dd), 2.38 (3H, s), 2.54 (3H, s), 2.73-2.84 (2H, m), 3.42 (3H, s), 3.55 (2H, t), 4.15 (2H, dd), 4.53-4.60 (1H, m), 6.87-8.38 (5H, m)It was prepared in substantially the same manner as in Example 60 using appropriate aniline derivatives and boronic acid derivatives (yield: 4%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, dd), 2.38 (3H, s), 2.54 (3H, s), 2.73-2.84 (2H, m), 3.42 (3H, s), 3.55 ( 2H, t), 4.15 (2H, dd), 4.53-4.60 (1H, m), 6.87-8.38 (5H, m)
실시예 62: 7-메틸-2-((4-메틸-6-(메틸술포닐)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 62: 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl Preparation of )-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000179
Figure PCTKR2022002310-appb-img-000179
Figure PCTKR2022002310-appb-img-000180
Figure PCTKR2022002310-appb-img-000180
실시예 1과 실질적으로 동일한 방법으로 4-메틸-6-(메틸티오)피리딘-3-아민을 사용하여 상기 반응식 26의 출발물질인 7-메틸-2-((4-메틸-6-(메틸티오)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸란-8-온을 제조하였다. In substantially the same manner as in Example 1, using 4-methyl-6-(methylthio)pyridin-3-amine, 7-methyl-2-((4-methyl-6-(methyl Prepared thio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-furan-8-one.
제조된 7-메틸-2-((4-메틸-6-(메틸티오)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 20 mg을 디클로로메탄 2 mL에 투입한 후, 0 ℃로 냉각하였다. mCPBA 18 mg을 분할하여 투입한 후, 상온에서 2 시간 동안 교반하였다. 반응물에 클로로포름 10 mL과 정제수 10 mL을 더 넣고, 클로로포름 층을 분리하여 마그네슘설페이트 처리하였다. 얻어진 클로로포름 층을 여과하고 농축하여 얻은 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 40 %). 1H-NMR (400MHz, CDCl3) δ 1.74 (2H, dd), 2.47 (3H, s), 2.75 (2H, m), 3.22 (3H, s), 3.44 (3H, s), 3.56 (2H, t), 4.14 (2H, dd), 4.57 (1H, m), 6.89-9.74 (4H, m)Prepared 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro 20 mg of -8H-purin-8-one was added to 2 mL of dichloromethane, and then cooled to 0 °C. 18 mg of mCPBA was divided and added, followed by stirring at room temperature for 2 hours. To the reaction product, 10 mL of chloroform and 10 mL of purified water were added, and the chloroform layer was separated and treated with magnesium sulfate. The resulting chloroform layer was filtered and concentrated, and the obtained residue was purified by Prep-HPLC to obtain the target compound (yield: 40%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, dd), 2.47 (3H, s), 2.75 (2H, m), 3.22 (3H, s), 3.44 (3H, s), 3.56 (2H, t), 4.14 (2H, dd), 4.57 (1H, m), 6.89-9.74 (4H, m)
실시예 63: 7-메틸-2-((4-메틸-6-(메틸술피닐)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 63: 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one {7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl Preparation of )-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000181
Figure PCTKR2022002310-appb-img-000181
실시예 62와 동일한 반응을 수행하여 제조하였다.It was prepared by performing the same reaction as in Example 62.
Figure PCTKR2022002310-appb-img-000182
Figure PCTKR2022002310-appb-img-000182
수득률: 46 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (2H, dd), 2.47 (3H, s), 2.75 (2H, m), 2.85 (3H, s), 3.42 (3H, s), 3.54 (2H, t), 4.14 (2H, d), 4.55 (1H, m), 6.74-9.48 (4H, m)Yield: 46%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (2H, dd), 2.47 (3H, s), 2.75 (2H, m), 2.85 (3H, s), 3.42 (3H, s), 3.54 (2H, t), 4.14 (2H, d), 4.55 (1H, m), 6.74-9.48 (4H, m)
실시예 64: N-(2-메톡시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {N-(2-methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 64: N-(2-Methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-di Hydro-7H-purin-2-yl)amino)picolinamide {N-(2-methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4) Preparation of -yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000183
Figure PCTKR2022002310-appb-img-000183
Figure PCTKR2022002310-appb-img-000184
Figure PCTKR2022002310-appb-img-000184
실시예 13에서 수득한 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리노니트릴 30 mg, 2-메톡시에탄-1-아민 0.01 mL 및 염화아연 1 mg을 클로로벤젠 1.5 ml에 투입한 후, 140 ℃에서 16 시간 동안 환류 교반하였다. 반응 종결 후 디클로로메탄 10 mL과 정제수 10 mL을 주입한 후, 디클로로메탄 층을 분리하였다. 유기층을 마그네슘설페이트 처리하고 여과하여 농축하였다. 얻은 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 32 %). 1H-NMR (400MHz, CDCl3) δ 1.74 (2H, dd), 2.42 (3H, s), 2.77 (2H, m), 3.42 (3H, s), 3.44 (3H, s), 3.56 (2H, t), 3.63 (2H, t), 4.15 (2H, dd), 4.50-4.59 (2H, m), 6.77-9.46 (5H, m)4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- obtained in Example 13) 30 mg of amino) picolinonitrile, 0.01 mL of 2-methoxyethan-1-amine, and 1 mg of zinc chloride were added to 1.5 ml of chlorobenzene, followed by stirring under reflux at 140° C. for 16 hours. After completion of the reaction, 10 mL of dichloromethane and 10 mL of purified water were injected, and the dichloromethane layer was separated. The organic layer was treated with magnesium sulfate, filtered and concentrated. The obtained residue was purified by Prep-HPLC to obtain the target compound (yield: 32%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, dd), 2.42 (3H, s), 2.77 (2H, m), 3.42 (3H, s), 3.44 (3H, s), 3.56 (2H, t), 3.63 (2H, t), 4.15 (2H, dd), 4.50-4.59 (2H, m), 6.77-9.46 (5H, m)
<실시예 65 내지 실시예 67><Examples 65 to 67>
실시예 65 내지 실시예 67에서는 실시예 64와 실질적으로 동일한 방법으로 적절한 아민 유도체를 사용하여 제조하였다.Examples 65 to 67 were prepared in substantially the same manner as in Example 64 using appropriate amine derivatives.
실시예 65: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-N-((테트라하이드로푸란-2-일)메틸)피콜린아미드 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide}의 제조Example 65: 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) Preparation of -8,9-dihydro-7H-purin-2-yl)amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide}
Figure PCTKR2022002310-appb-img-000185
Figure PCTKR2022002310-appb-img-000185
수득률: 27 %; 1H-NMR (400MHz, CDCl3) δ 1.60-2.05 (6H, m), 2.42 (3H, s), 2.76 (2H, m), 3.42 (3H, s), 3.44-3.59 (3H, m), 3.69-3.96 (3H, m), 4.07-4.17 (3H, m), 4.52-4.60 (1H, m), 6.78-9.44 (5H, m)Yield: 27%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.60-2.05 (6H, m), 2.42 (3H, s), 2.76 (2H, m), 3.42 (3H, s), 3.44-3.59 (3H, m), 3.69-3.96 (3H, m), 4.07-4.17 (3H, m), 4.52-4.60 (1H, m), 6.78-9.44 (5H, m)
실시예 66: N-(2-히드록시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 66: N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-di Hydro-7H-purin-2-yl)amino)picolinamide {N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4) Preparation of -yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000186
Figure PCTKR2022002310-appb-img-000186
수득률: 35 %; 1H-NMR(400MHz, CDCl3) δ 1.75 (2H, dd), 2.43 (3H, s), 2.75 (2H, m), 3.43 (3H, s), 3.56 (2H, t), 3.65 (2H, q), 3.85 (2H, m), 4.52-4.60 (1H, m), 6.84-9.47 (5H, m)Yield: 35%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.75 (2H, dd), 2.43 (3H, s), 2.75 (2H, m), 3.43 (3H, s), 3.56 (2H, t), 3.65 (2H, q), 3.85 (2H, m), 4.52-4.60 (1H, m), 6.84-9.47 (5H, m)
실시예 67: N-(2,2-디메톡시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {N-(2,2-dimethoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 67: N-(2,2-dimethoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9 -dihydro-7H-purin-2-yl)amino)picolinamide {N-(2,2-dimethoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H) Preparation of -pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000187
Figure PCTKR2022002310-appb-img-000187
수득률: 13 %; 1H-NMR(400MHz, CDCl3) δ 1.74 (2H, dd), 2.42 (3H, s), 2.76 (2H, m), 3.41 (3H, s), 3.42 (3H, s), 3.53-3.60 (4H, m), 3.67 (2H, q), 4.15 (2H, dd), 4.52-4.60 (1H, m), 6.78-9.45 (5H, s)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.74 (2H, dd), 2.42 (3H, s), 2.76 (2H, m), 3.41 (3H, s), 3.42 (3H, s), 3.53-3.60 ( 4H, m), 3.67 (2H, q), 4.15 (2H, dd), 4.52-4.60 (1H, m), 6.78-9.45 (5H, s)
실시예 68: 4-메틸-N-(1-메틸-1H-피라졸-4-일)-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드 {4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}의 제조Example 68: 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) )-8,9-dihydro-7H-purin-2-yl)amino)picolinamide {4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl Preparation of -8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000188
Figure PCTKR2022002310-appb-img-000188
Figure PCTKR2022002310-appb-img-000189
Figure PCTKR2022002310-appb-img-000189
실시예 16의 메틸 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리네이트 16.6 mg 및 1N-수산화칼륨 수용액 1 mL을 에탄올 1 mL 및 정제수 1 mL인 혼합용매에 넣고, 50 ℃에서 4 시간 동안 교반하였다. 반응 종료 후, 에틸아세테이트 10 mL 및 1N-염산수용액 10 mL을 주입한 후, 에틸아세테이트 층을 분리하고 농축하였다. 별도의 정제단계 없이 Mass 확인 후, 다음 단계의 반응을 진행하였다. Methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl of Example 16) )Amino)picolinate 16.6 mg and 1N-potassium hydroxide aqueous solution 1mL were put in a mixed solvent of 1mL ethanol and 1mL purified water, and the mixture was stirred at 50°C for 4 hours. After completion of the reaction, 10 mL of ethyl acetate and 10 mL of a 1N-hydrochloric acid solution were injected, and the ethyl acetate layer was separated and concentrated. After confirming the mass without a separate purification step, the reaction of the next step was performed.
얻어진 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린산 20 mg, 1-메틸-1H-피라졸-4-아민 5 mg, HATU 20 mg 및 디이소프로필에틸아민 0.028 mL을 디메틸포름아미드 2 mL에 넣고, 16 시간 동안 상온 교반하였다. 반응 종결 후, 에틸아세테이트 10 mL 및 정제수 10 mL을 주입한 후, 에틸아세테이트 층을 분리하고 농축하였다. 얻은 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 14 %). 1H-NMR (400MHz, CDCl3) δ 1.76 (2H, d), 2.46 (3H, s), 2.74 (2H, m), 3.43 (3H,s), 3.55 (2H, t), 3.92 (3H, s), 4.15 (2H, dd), 4.53-4.59 (1H, m), 7.58-9.73 (6H, m)Obtained 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)p 20 mg of cholic acid, 5 mg of 1-methyl-1H-pyrazol-4-amine, 20 mg of HATU and 0.028 mL of diisopropylethylamine were added to 2 mL of dimethylformamide, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, 10 mL of ethyl acetate and 10 mL of purified water were injected, and the ethyl acetate layer was separated and concentrated. The obtained residue was purified by Prep-HPLC to obtain the target compound (yield: 14%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.76 (2H, d), 2.46 (3H, s), 2.74 (2H, m), 3.43 (3H,s), 3.55 (2H, t), 3.92 (3H, s), 4.15 (2H, dd), 4.53-4.59 (1H, m), 7.58-9.73 (6H, m)
실시예 69: 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-N-(옥세탄-3-일)피콜린아미드 {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-N-(oxetan-3-yl)picolinamide}의 제조Example 69: 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)-N-(oxetan-3-yl)picolinamide {4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9 Preparation of -dihydro-7H-purin-2-yl)amino)-N-(oxetan-3-yl)picolinamide}
Figure PCTKR2022002310-appb-img-000190
Figure PCTKR2022002310-appb-img-000190
실시예 68과 실질적으로 동일한 방법으로 옥세탄-3-일-아민를 사용하여 제조하였다(수득률: 42 %). 1H-NMR (400MHz, CDCl3) δ 1.75 (2H, dd), 2.43 (3H, s), 2.77 (2H, m), 3.43 (3H,s), 3.56 (2H, t), 4.16 (2H, dd), 4.53-4.61 (1H, m), 4.71 (2H, t), 5.01 (2H, t), 5.30 (1H, s), 6.84-9.52 (5H, m)It was prepared using oxetan-3-yl-amine in substantially the same manner as in Example 68 (yield: 42%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.75 (2H, dd), 2.43 (3H, s), 2.77 (2H, m), 3.43 (3H,s), 3.56 (2H, t), 4.16 (2H, dd), 4.53-4.61 (1H, m), 4.71 (2H, t), 5.01 (2H, t), 5.30 (1H, s), 6.84-9.52 (5H, m)
실시예 70: 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 70: 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one {5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000191
Figure PCTKR2022002310-appb-img-000191
2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 50 mg, 7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-아민 53 mg, Pd(dba)2 15 mg, BINAP 33 mg 및 세슘카보네이트 175 mg을 다이옥산 3 mL에 넣고, 120 ℃로 15 분 동안 마이크로웨이브를 조사하여 반응하였다. 반응 종결 후 셀라이트 여과하고 농축한 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 41 %). 1H-NMR (400MHz, CDCl3) δ 1.51 (2H, d), 2.40 (3H, s), 2.51 (3H, s), 2.95 (2H, m), 3.52 (2H, t), 4.01 (2H, d), 5.53 (1H, t), 6.32 (1H, s), 6.97 (1H, s), 7.64 (1H, s), 8.31 (1H, s), 8.66 (1H, s), 9.34 (1H, s)2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 50 mg, 7-methyl-[1, 2,4]triazolo[1,5-a]pyridin-6-amine 53 mg, Pd(dba) 2 15 mg, BINAP 33 mg, and cesium carbonate 175 mg were placed in 3 mL of dioxane, and heated to 120 ° C for 15 minutes. It reacted by irradiation with microwaves. After completion of the reaction, the concentrated residue was purified by celite filtration and Prep-HPLC to obtain the target compound (yield: 41%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.51 (2H, d), 2.40 (3H, s), 2.51 (3H, s), 2.95 (2H, m), 3.52 (2H, t), 4.01 (2H, d), 5.53 (1H, t), 6.32 (1H, s), 6.97 (1H, s), 7.64 (1H, s), 8.31 (1H, s), 8.66 (1H, s), 9.34 (1H, s) )
<실시예 71 내지 실시예 101><Examples 71 to 101>
실시예 71 내지 실시예 101에서는 실시예 70과 실질적으로 동일한 방법으로 적절한 제조예의 화합물과 아민 유도체를 사용하여 제조하였다.Examples 71 to 101 were prepared in substantially the same manner as in Example 70, using the appropriate compounds and amine derivatives.
실시예 71: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 71: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-thiopyran-4- yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9- Preparation of (tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000192
Figure PCTKR2022002310-appb-img-000192
수득률: 8 %; 1H-NMR (400MHz, CDCl3) δ 2.16 (2H, m), 2.60 (3H, s), 2.81 (4H, m), 2.91 (2H, q), 3.44 (3H, s), 4.34 (1H, t), 7.08 (1H, s), 7.80 (1H, s), 7.99 (1H, s), 9.06 (1H, s)Yield: 8%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.16 (2H, m), 2.60 (3H, s), 2.81 (4H, m), 2.91 (2H, q), 3.44 (3H, s), 4.34 (1H, t), 7.08 (1H, s), 7.80 (1H, s), 7.99 (1H, s), 9.06 (1H, s)
실시예 72: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 72: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9 -dihydro-8H-purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl) Preparation of -7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000193
Figure PCTKR2022002310-appb-img-000193
수득률: 17 %; 1H-NMR (400MHz, CDCl3) δ 2.14 (2H, m), 2.49 (3H, s), 2.81 (3H, s), 2.76-2.92 (6H, m), 3.41 (3H, s), 4.31 (1H, t), 6.92 (1H, s), 7.76 (1H, s), 7.90 (1H, s), 8.82 (1H, s)Yield: 17%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.14 (2H, m), 2.49 (3H, s), 2.81 (3H, s), 2.76-2.92 (6H, m), 3.41 (3H, s), 4.31 ( 1H, t), 6.92 (1H, s), 7.76 (1H, s), 7.90 (1H, s), 8.82 (1H, s)
실시예 73: 7-메틸-2-((7-메틸퀴놀린-6-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 73: 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purine -8-one {7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8- manufacture of one}
Figure PCTKR2022002310-appb-img-000194
Figure PCTKR2022002310-appb-img-000194
수득률: 13 %; 1H-NMR (400MHz, CDCl3) δ 2.19 (2H, m), 2.61 (3H, s), 2.85 (3H, t), 2.93 (3H, t), 3.44 (3H, s), 4.37 (1H, t), 7.16 (1H, s), 7.34 (1H, q), 7.93 (1H, s), 7.97 (1H, s), 8.39 (1H, d), 8.76 (1H, d), 8.91 (1H, s)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.19 (2H, m), 2.61 (3H, s), 2.85 (3H, t), 2.93 (3H, t), 3.44 (3H, s), 4.37 (1H, t), 7.16 (1H, s), 7.34 (1H, q), 7.93 (1H, s), 7.97 (1H, s), 8.39 (1H, d), 8.76 (1H, d), 8.91 (1H, s) )
실시예 74: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 74: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl) -7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro [3.5] Preparation of nonan-7-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000195
Figure PCTKR2022002310-appb-img-000195
수득률: 34 %; 1H-NMR (400MHz, CDCl3) δ 1.55 (2H, t), 1.72 (2H, br), 2.21 (3H, s), 2.27 (4H, q), 3.37 (3H, s), 4.21 (1H, t), 4.37 (2H, s), 4.46 (2H, s), 5.93 (2H, s), 6.45 (1H, s), 6.71 (1H, s), 7.25 (1H, s), 7.81 (1H, s)Yield: 34%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.55 (2H, t), 1.72 (2H, br), 2.21 (3H, s), 2.27 (4H, q), 3.37 (3H, s), 4.21 (1H, t), 4.37 (2H, s), 4.46 (2H, s), 5.93 (2H, s), 6.45 (1H, s), 6.71 (1H, s), 7.25 (1H, s), 7.81 (1H, s) )
실시예 75: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 75: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7, 9-dihydro-8H-purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7 Preparation of -yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000196
Figure PCTKR2022002310-appb-img-000196
수득률: 69 %; 1H-NMR (400MHz, CDCl3) δ 1.58 (2H, t), 1.78 (2H, br), 2.30 (4H, q), 2.44 (3H, s), 2.81 (3H, s), 3.39 (3H, s), 4.25 (1H, t), 4.38 (2H, s), 4.43 (2H, s), 6.77 (1H, s), 7.77 (1H, s), 7.87 (1H, s), 8.47 (1H, s)Yield: 69%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.58 (2H, t), 1.78 (2H, br), 2.30 (4H, q), 2.44 (3H, s), 2.81 (3H, s), 3.39 (3H, s), 4.25 (1H, t), 4.38 (2H, s), 4.43 (2H, s), 6.77 (1H, s), 7.77 (1H, s), 7.87 (1H, s), 8.47 (1H, s) )
실시예 76: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 76: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(2-oxaspiro[3.5]nonane-7 -yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9 Preparation of -(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000197
Figure PCTKR2022002310-appb-img-000197
수득률: 54 %; 1H-NMR (400MHz, CDCl3) δ 1.66 (2H, m), 1.83 (2H, d), 2.39 (4H, m), 2.57 (3H, s), 3.43 (3H, s), 4.32 (1H, m), 4.41 (2H, s), 4.63 (2H, s), 7.06 (1H, s), 7.80 (1H, s), 7.97 (1H, s), 8.86 (1H, s)Yield: 54%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.66 (2H, m), 1.83 (2H, d), 2.39 (4H, m), 2.57 (3H, s), 3.43 (3H, s), 4.32 (1H, m), 4.41 (2H, s), 4.63 (2H, s), 7.06 (1H, s), 7.80 (1H, s), 7.97 (1H, s), 8.86 (1H, s)
실시예 77: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 77: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H -Purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin- Preparation of 8-one}
Figure PCTKR2022002310-appb-img-000198
Figure PCTKR2022002310-appb-img-000198
수득률: 68 %; 1H-NMR (400MHz, CDCl3) δ 2.46 (3H, s), 2.54 (4H, br), 2.75 (2H, t), 2.81 (3H, s), 3.41 (3H, s), 3.60 (4H, t), 4.03 (2H, t), 6.84 (1H, s), 7.76 (1H, s), 7.88 (1H, s), 8.64 (1H, s)Yield: 68%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.46 (3H, s), 2.54 (4H, br), 2.75 (2H, t), 2.81 (3H, s), 3.41 (3H, s), 3.60 (4H, t), 4.03 (2H, t), 6.84 (1H, s), 7.76 (1H, s), 7.88 (1H, s), 8.64 (1H, s)
실시예 78: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 78: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9-di Hydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9- Preparation of dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000199
Figure PCTKR2022002310-appb-img-000199
수득률: 64 %; 1H-NMR (400MHz, CDCl3) δ 2.22 (3H, s), 2.53 (4H, br), 2.72 (2H, t), 3.39 (3H, s), 3.61 (4H, t), 3.99 (2H, t), 5.92 (2H, s), 6.46 (1H, s), 6.69 (1H, s), 7.39 (1H, s), 7.81 (1H, s)Yield: 64%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.22 (3H, s), 2.53 (4H, br), 2.72 (2H, t), 3.39 (3H, s), 3.61 (4H, t), 3.99 (2H, t), 5.92 (2H, s), 6.46 (1H, s), 6.69 (1H, s), 7.39 (1H, s), 7.81 (1H, s)
실시예 79: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purin-8-one}의 제조Example 79: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purine -8-one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purin-8-one } manufacturing
Figure PCTKR2022002310-appb-img-000200
Figure PCTKR2022002310-appb-img-000200
수득률: 31 %; 1H-NMR (400MHz, CDCl3) δ 2.23 (3H, s), 3.36 (3H, s), 3.52 (4H, m), 3.93 (4H, t), 5.93 (2H, s), 6.53 (1H, s), 6.70 (1H, s), 7.35 (1H, s), 7.82 (1H, s)Yield: 31%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.23 (3H, s), 3.36 (3H, s), 3.52 (4H, m), 3.93 (4H, t), 5.93 (2H, s), 6.53 (1H, s), 6.70 (1H, s), 7.35 (1H, s), 7.82 (1H, s)
실시예 80: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one}의 제조Example 80: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purine-8- Preparation of one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000201
Figure PCTKR2022002310-appb-img-000201
수득률: 51 %; 1H-NMR (400MHz, CDCl3) δ 2.47 (3H, s), 2.80 (3H, s), 3.39 (3H, s), 3.54 (4H, m), 3.94 (4H, t), 6.93 (1H, s), 7.76 (1H, s), 7.90 (1H, s), 8.71 (1H, s)Yield: 51%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.47 (3H, s), 2.80 (3H, s), 3.39 (3H, s), 3.54 (4H, m), 3.94 (4H, t), 6.93 (1H, s), 7.76 (1H, s), 7.90 (1H, s), 8.71 (1H, s)
실시예 81: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 81: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[2.5]octan-6-yl) -7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro Preparation of [2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000202
Figure PCTKR2022002310-appb-img-000202
수득률: 28 %; 1H-NMR (400MHz, CDCl3) δ 0.40-0.42 (4H, m), 1.04 (2H, d), 1.83 (2H, d), 2.00 (2H, t), 2.58 (3H, s), 2.63 (2H, m), 3.44 (3H, s), 4.42 (1H, m), 7.10 (1H, s), 7.80 (1H, s), 7.96 (1H, s), 8.98 (1H, s)Yield: 28%; 1 H-NMR (400 MHz, CDCl 3 ) δ 0.40-0.42 (4H, m), 1.04 (2H, d), 1.83 (2H, d), 2.00 (2H, t), 2.58 (3H, s), 2.63 (2H, m), 3.44 (3H, s) ), 4.42 (1H, m), 7.10 (1H, s), 7.80 (1H, s), 7.96 (1H, s), 8.98 (1H, s)
실시예 82: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 82: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7, 9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan- Preparation of 6-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000203
Figure PCTKR2022002310-appb-img-000203
수득률: 77 %; 1H-NMR (400MHz, CDCl3) δ 0.33 (4H, m), 0.96 (2H, d), 1.74 (2H, d), 1.94 (2H, t), 2.24 (3H, s), 2.53 (2H, q), 3.38 (3H, s), 4.30 (1H, m), 5.93 (2H, s), 6.49 (1H, s), 6.70 (1H, s), 7.43 (1H, s), 7.80 (1H, s)Yield: 77%; 1 H-NMR (400 MHz, CDCl 3 ) δ 0.33 (4H, m), 0.96 (2H, d), 1.74 (2H, d), 1.94 (2H, t), 2.24 (3H, s), 2.53 (2H, q), 3.38 (3H, s), 4.30 (1H, m), 5.93 (2H, s), 6.49 (1H, s), 6.70 (1H, s), 7.43 (1H, s), 7.80 (1H, s)
실시예 83: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 83: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7 ,9-dihydro-8H-purin-8-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4 Preparation of -yl)methyl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000204
Figure PCTKR2022002310-appb-img-000204
수득률: 69 %; 1H-NMR (400MHz, CDCl3) δ 1.47 (2H, q), 1.62 (2H, d), 2.22 (1H, m), 2.47 (3H, s), 2.80 (3H, s), 3.34 (2H, d), 3.41 (3H, s), 3.80 (2H, d), 4.00 (2H, d), 6.88 (1H, s), 7.75 (1H, s), 7.88 (1H, s), 8.69 (1H, s)Yield: 69%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.47 (2H, q), 1.62 (2H, d), 2.22 (1H, m), 2.47 (3H, s), 2.80 (3H, s), 3.34 (2H, d), 3.41 (3H, s), 3.80 (2H, d), 4.00 (2H, d), 6.88 (1H, s), 7.75 (1H, s), 7.88 (1H, s), 8.69 (1H, s)
실시예 84: 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 84: 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl )-7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro Preparation of -2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000205
Figure PCTKR2022002310-appb-img-000205
수득률: 41 %; 1H-NMR (400MHz, CDCl3) δ 1.45 (2H, q), 1.60 (2H, d), 2.19 (1H, m), 2.23 (3H, s), 3.35 (2H, d), 3.39 (3H, s), 3.77 (2H, d), 3.97 (2H, d), 5.93 (2H, s), 6.49 (1H, s), 6.70 (1H, s), 7.42 (1H, s), 7.82 (1H, s)Yield: 41%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.45 (2H, q), 1.60 (2H, d), 2.19 (1H, m), 2.23 (3H, s), 3.35 (2H, d), 3.39 (3H, s), 3.77 (2H, d), 3.97 (2H, d), 5.93 (2H, s), 6.49 (1H, s), 6.70 (1H, s), 7.42 (1H, s), 7.82 (1H, s)
실시예 85: 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 85: 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-((tetrahydro-2H-pyran-4- yl)methyl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000206
Figure PCTKR2022002310-appb-img-000206
수득률: 56 %; 1H-NMR (400MHz, CDCl3) δ 1.51 (2H, q), 1.65 (2H, d), 2.27 (1H, m), 2.58 (3H, s), 3.39 (2H, t), 3.46 (3H, s), 3.88 (2H, d), 3.99 (2H, d), 7.10 (1H, s), 7.79 (1H, s), 7.98 (1H, s), 9.08 (1H, s)Yield: 56%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.51 (2H, q), 1.65 (2H, d), 2.27 (1H, m), 2.58 (3H, s), 3.39 (2H, t), 3.46 (3H, s), 3.88 (2H, d), 3.99 (2H, d), 7.10 (1H, s), 7.79 (1H, s), 7.98 (1H, s), 9.08 (1H, s)
실시예 86: 7-메틸-2-((7-메틸퀴놀린-6-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 86: 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H -Purin-8-one {7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H Preparation of -purin-8-one}
Figure PCTKR2022002310-appb-img-000207
Figure PCTKR2022002310-appb-img-000207
수득률: 43 %; 1H-NMR (400MHz, CDCl3) δ 1.51 (2H, q), 1.65 (2H, d), 2.25 (1H, m), 2.59 (3H, s), 3.38 (2H, t), 3.44 (3H, s), 3.85 (2H, d), 4.00 (2H, d), 7.08 (1H, s), 7.33 (1H, q), 7.95 (2H, d), 8.06 (1H, d), 8.76 (2H, d)Yield: 43%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.51 (2H, q), 1.65 (2H, d), 2.25 (1H, m), 2.59 (3H, s), 3.38 (2H, t), 3.44 (3H, s), 3.85 (2H, d), 4.00 (2H, d), 7.08 (1H, s), 7.33 (1H, q), 7.95 (2H, d), 8.06 (1H, d), 8.76 (2H, d)
실시예 87: 7-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}의 제조Example 87: 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-9-((tetrahydro-2H- Pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin) Preparation of -6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000208
Figure PCTKR2022002310-appb-img-000208
수득률: 17 %; 1H-NMR (400MHz, CDCl3) δ 1.46 (2H, q), 1.60 (2H, d), 2.21 (1H, m), 2.22 (3H, s), 3.38 (2H, t), 3.39 (3H, s), 3.77 (2H, d), 3.99 (2H, d), 4.24 (4H, s), 6.51 (1H, s), 6.71 (1H, q), 7.51 (2H, d), 7.82 (1H, d)Yield: 17%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.46 (2H, q), 1.60 (2H, d), 2.21 (1H, m), 2.22 (3H, s), 3.38 (2H, t), 3.39 (3H, s), 3.77 (2H, d), 3.99 (2H, d), 4.24 (4H, s), 6.51 (1H, s), 6.71 (1H, q), 7.51 (2H, d), 7.82 (1H, d)
실시예 88: 9-(2-메톡시에틸)-7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-7,9-디하이드로-8H-푸린-8-온 {9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-7,9-dihydro-8H-purin-8-one}의 제조Example 88: 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-7,9 -dihydro-8H-purin-8-one {9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000209
Figure PCTKR2022002310-appb-img-000209
수득률: 14 %; 1H-NMR (400MHz, CDCl3) δ 2.58 (3H, s), 3.40 (3H, s), 3.46 (3H, s), 3.83 (2H, t), 4.18 (2H, t), 7.10 (1H, s), 7.79 (1H, s), 7.98 (1H, s), 9.09 (1H, s)Yield: 14%; 1 H-NMR (400 MHz, CDCl 3 ) δ 2.58 (3H, s), 3.40 (3H, s), 3.46 (3H, s), 3.83 (2H, t), 4.18 (2H, t), 7.10 (1H, s), 7.79 (1H, s), 7.98 (1H, s), 9.09 (1H, s)
실시예 89: 7-메틸-2-((6-메틸-2-옥소-2,3-디하이드로-1H-벤조[d]이미다졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 89: 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one {7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d Preparation of ]imidazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000210
Figure PCTKR2022002310-appb-img-000210
수득률: 11 %; 1H-NMR (400MHz, CD3OD) δ 1.68 (2H, d), 2.27 (3H, s), 2.66 (2H, qd), 3.31 (3H, s), 3.48 (2H, t), 4.04 (2H, dd), 4.49 (1H, tt), 6.93 (1H, s), 7.22 (1H, s), 7.86 (1H, s)Yield: 11%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.68 (2H, d), 2.27 (3H, s), 2.66 (2H, qd), 3.31 (3H, s), 3.48 (2H, t), 4.04 (2H) , dd), 4.49 (1H, tt), 6.93 (1H, s), 7.22 (1H, s), 7.86 (1H, s)
실시예 90: 6-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 90: 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one {6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000211
Figure PCTKR2022002310-appb-img-000211
수득률: 35 %; 1H-NMR (400MHz, CDCl3) δ 1.57 (2H, m), 2.19 (3H, s), 2.51 (3H, s), 3.03 (2H, q), 3.56 (2H, t), 4.07 (2H, d), 5.59 (1H, t), 6.94 (1H, s), 7.39 (1H, s), 7.63 (1H, s), 8.30 (1H, s), 8.51 (1H, s), 9.41 (1H, s)Yield: 35%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.57 (2H, m), 2.19 (3H, s), 2.51 (3H, s), 3.03 (2H, q), 3.56 (2H, t), 4.07 (2H, d), 5.59 (1H, t), 6.94 (1H, s), 7.39 (1H, s), 7.63 (1H, s), 8.30 (1H, s), 8.51 (1H, s), 9.41 (1H, s) )
실시예 91: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 91: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, 3-d]pyrimidin-7(8H)-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4- Preparation of yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000212
Figure PCTKR2022002310-appb-img-000212
수득률: 33 %; 1H-NMR (400MHz, CDCl3) δ 1.24 (2H, m), 2.39 (3H, s), 2.49 (3H, s), 2.82 (3H, s), 3.11 (2H, m), 3.52 (2H, t), 4.12 (2H, d), 5.60 (1H, t), 6.29 (1H, s), 7.20 (1H, s), 7.81 (1H, s), 8.60 (1H, s), 8.64 (1H, s)Yield: 33%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24 (2H, m), 2.39 (3H, s), 2.49 (3H, s), 2.82 (3H, s), 3.11 (2H, m), 3.52 (2H, t), 4.12 (2H, d), 5.60 (1H, t), 6.29 (1H, s), 7.20 (1H, s), 7.81 (1H, s), 8.60 (1H, s), 8.64 (1H, s) )
실시예 92: 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 92: 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, 3-d]pyrimidin-7(8H)-one {2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4- Preparation of yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000213
Figure PCTKR2022002310-appb-img-000213
수득률: 25 %; 1H-NMR (400MHz, CDCl3) δ 1.50 (2H, d), 2.37 (3H, s), 2.42 (3H, s), 2.82 (3H, s), 2.92 (2H, q), 3.46 (2H, t), 3.97 (2H, d), 5.54 (1H, t), 6.25 (1H, s), 7.10 (1H, s), 7.69 (1H, s), 8.38 (1H, s), 8.62 (1H, s)Yield: 25%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.50 (2H, d), 2.37 (3H, s), 2.42 (3H, s), 2.82 (3H, s), 2.92 (2H, q), 3.46 (2H, t), 3.97 (2H, d), 5.54 (1H, t), 6.25 (1H, s), 7.10 (1H, s), 7.69 (1H, s), 8.38 (1H, s), 8.62 (1H, s) )
실시예 93: 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 93: 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )pyrido[2,3-d]pyrimidin-7(8H)-one {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000214
Figure PCTKR2022002310-appb-img-000214
수득률: 16 %; 1H-NMR (400MHz, CDCl3) δ 1.55 (2H, d), 2.42 (3H, s), 2.60 (3H, s), 3.05 (2H, qd), 3.66 (2H, t), 4.11 (2H, dd), 5.71 (1H, s), 6.33 (1H, s), 7.33 (1H, s), 7.86 (1H, s), 8.71 (1H, s), 8.90 (1H, s)Yield: 16%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.55 (2H, d), 2.42 (3H, s), 2.60 (3H, s), 3.05 (2H, qd), 3.66 (2H, t), 4.11 (2H, dd), 5.71 (1H, s), 6.33 (1H, s), 7.33 (1H, s), 7.86 (1H, s), 8.71 (1H, s), 8.90 (1H, s)
실시예 94: 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 94: 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido [2,3-d]pyrimidin-7(8H)-one {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro- Preparation of 2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000215
Figure PCTKR2022002310-appb-img-000215
수득률: 19 %; 1H-NMR (400MHz, CDCl3) δ 1.45 (2H, d), 2.22 (3H, s), 2.42 (3H, s), 2.53 (2H, m), 3.46 (2H, t), 4.02 (2H, d), 5.50 (1H, t), 5.59 (2H, s), 6.23 (1H, s), 6.75 (1H, s), 6.81 (1H, s), 8.58 (1H, s)Yield: 19%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.45 (2H, d), 2.22 (3H, s), 2.42 (3H, s), 2.53 (2H, m), 3.46 (2H, t), 4.02 (2H, d), 5.50 (1H, t), 5.59 (2H, s), 6.23 (1H, s), 6.75 (1H, s), 6.81 (1H, s), 8.58 (1H, s)
실시예 95: 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((6-bromo-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 95: 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one {2-((6-bromo-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000216
Figure PCTKR2022002310-appb-img-000216
수득률: 36 %; 1H-NMR (400MHz, CDCl3) δ 1.48 (2H, d), 2.34 (3H, s), 2.38 (3H, s), 2.92 (2H, qd), 3.48 (2H, t), 4.06 (2H, dd), 5.48 (1H, tt), 6.29 (1H, s), 6.84 (1H, s), 7.41 (1H, s), 8.61 (1H, s), 8.72 (1H, s)Yield: 36%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48 (2H, d), 2.34 (3H, s), 2.38 (3H, s), 2.92 (2H, qd), 3.48 (2H, t), 4.06 (2H, dd), 5.48 (1H, tt), 6.29 (1H, s), 6.84 (1H, s), 7.41 (1H, s), 8.61 (1H, s), 8.72 (1H, s)
실시예 96: 5-에틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 96: 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one {5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000217
Figure PCTKR2022002310-appb-img-000217
수득률: 24 %; 1H-NMR (400MHz, CDCl3) δ 1.32 (3H, t), 1.51 (2H, d), 2.50 (3H, s), 2.75 (2H, q), 2.96 (2H, q), 3.51 (2H, t), 4.03 (2H, dd), 5.52 (1H, t), 6.34 (1H, s), 7.01 (1H, s), 7.63 (1H, s), 8.30 (1H, s), 8.70 (1H, s), 9.32 (1H, br s)Yield: 24%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32 (3H, t), 1.51 (2H, d), 2.50 (3H, s), 2.75 (2H, q), 2.96 (2H, q), 3.51 (2H, t), 4.03 (2H, dd), 5.52 (1H, t), 6.34 (1H, s), 7.01 (1H, s), 7.63 (1H, s), 8.30 (1H, s), 8.70 (1H, s) ), 9.32 (1H, br s)
실시예 97: 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 97: 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one {2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000218
Figure PCTKR2022002310-appb-img-000218
수득률: 40 %; 1H-NMR (400MHz, CDCl3) δ 1.29 (3H, t), 1.47 (2H, dd), 2.74 (2H, q), 2.92 (2H, qd), 3.47 (2H, t), 4.04 (2H, dd), 5.47 (1H, tt), 6.31 (1H, s), 7.02 (1H, s), 7.40 (1H, s), 8.65 (1H, s), 8.69 (1H, s)Yield: 40%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29 (3H, t), 1.47 (2H, dd), 2.74 (2H, q), 2.92 (2H, qd), 3.47 (2H, t), 4.04 (2H, dd), 5.47 (1H, tt), 6.31 (1H, s), 7.02 (1H, s), 7.40 (1H, s), 8.65 (1H, s), 8.69 (1H, s)
실시예 98: 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온 {8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 98: 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one {8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2, Preparation of 4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000219
Figure PCTKR2022002310-appb-img-000219
수득률: 33 %; 1H-NMR (400MHz, CDCl3) δ 1.60 (3H, s), 1.64 (2H, d), 1.87 (2H, m), 2.13 (2H, m), 2.40 (3H, s), 2.49 (3H, s), 2.93 (2H, m), 5.38 (1H, t), 6.32 (1H, s), 6.91 (1H, s), 7.63 (1H, s), 8.30 (1H, s), 8.67 (1H, s), 9.35 (1H, br s)Yield: 33%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.60 (3H, s), 1.64 (2H, d), 1.87 (2H, m), 2.13 (2H, m), 2.40 (3H, s), 2.49 (3H, s), 2.93 (2H, m), 5.38 (1H, t), 6.32 (1H, s), 6.91 (1H, s), 7.63 (1H, s), 8.30 (1H, s), 8.67 (1H, s) ), 9.35 (1H, br s)
실시예 99: 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 99: 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H) -pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one {5-methyl-2-((7-methyl-[1,2,4]triazolo[1 Preparation of ,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000220
Figure PCTKR2022002310-appb-img-000220
수득률: 32 %; 1H-NMR (400MHz, CDCl3) δ 1.47 (4H, m), 2.43 (3H, s), 2.53 (3H, s), 3.21 (2H, td), 3.92 (2H, d), 4.28 (2H, d), 6.37 (1H, s), 7.02 (1H, s), 7.63 (1H, s), 8.28 (1H, s), 8.69 (1H, s)Yield: 32%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.47 (4H, m), 2.43 (3H, s), 2.53 (3H, s), 3.21 (2H, td), 3.92 (2H, d), 4.28 (2H, d), 6.37 (1H, s), 7.02 (1H, s), 7.63 (1H, s), 8.28 (1H, s), 8.69 (1H, s)
실시예 100: 8-사이클로헥실-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온 {8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 100: 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2, 3-d]pyrimidin-7(8H)-one {8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl Preparation of )amino)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000221
Figure PCTKR2022002310-appb-img-000221
수득률: 17 %; 1H-NMR (400MHz, CDCl3) δ 1.36-1.76 (10H, m), 2.38 (3H, s), 2.39 (3H, s), 5.51 (1H, s), 6.30 (1H, s), 6.90 (1H, s), 7.64 (1H, s), 8.30 (1H, s), 8.64 (1H, s)Yield: 17%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.76 (10H, m), 2.38 (3H, s), 2.39 (3H, s), 5.51 (1H, s), 6.30 (1H, s), 6.90 ( 1H, s), 7.64 (1H, s), 8.30 (1H, s), 8.64 (1H, s)
실시예 101: (1R,4R)-4-(5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)-7-옥소피리도[2,3-d]피리미딘-8(7H)-일)사이클로헥실아세테이트 {(1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate}의 제조Example 101: (1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)- 7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate {(1R,4R)-4-(5-methyl-2-((7-methyl-[1, Preparation of 2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate}
Figure PCTKR2022002310-appb-img-000222
Figure PCTKR2022002310-appb-img-000222
수득률: 16 %; 1H-NMR (400MHz, CDCl3) δ 1.52-1.69 (4H, m), 2.05 (5H, m), 2.39 (3H, s), 2.52 (3H, s), 2.75 (2H, m), 5.32 (1H, m), 6.30 (1H, s), 6.90 (1H, s), 7.66 (1H, s), 8.31 (1H, s), 8.65 (1H, s)Yield: 16%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.52-1.69 (4H, m), 2.05 (5H, m), 2.39 (3H, s), 2.52 (3H, s), 2.75 (2H, m), 5.32 ( 1H, m), 6.30 (1H, s), 6.90 (1H, s), 7.66 (1H, s), 8.31 (1H, s), 8.65 (1H, s)
실시예 102: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 102: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8- Dihydropyrido[2,3-d]pyrimidin-7(6H)-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro Preparation of -2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000223
Figure PCTKR2022002310-appb-img-000223
실시예 91에서 제조한 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 20 mg 및 LiBH4 10 mg을 THF 2 mL에 투입하였다. 상온에서 4 시간 동안 교반한 후, 에틸아세테이트 10 mL, 정제수 10 mL을 주입하였다. 에틸아세테이트 층을 분리하고 마그네슘설페이트 처리한 후, 여과하여 농축하였다. 얻어진 잔사물을 Prep-HPLC로 정제하여 표제 화합물을 수득하였다(수득률: 50 %). 1H-NMR (400MHz, CDCl3) δ 1.52 (2H, d), 1.93 (3H, s), 2.43 (3H, s), 2.83 (3H, s), 3.14 (2H, m), 3.47 (2H, t), 4.03 (2H, dd), 4.36 (2H, s), 5.61 (1H, s), 5.89 (1H, s), 7.82 (1H, s), 7.93 (1H, s)2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ 20 mg of 2,3-d]pyrimidin-7(8H)-one and 10 mg of LiBH 4 were added to 2 mL of THF. After stirring at room temperature for 4 hours, 10 mL of ethyl acetate and 10 mL of purified water were injected. The ethyl acetate layer was separated, treated with magnesium sulfate, filtered and concentrated. The obtained residue was purified by Prep-HPLC to obtain the title compound (yield: 50%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.52 (2H, d), 1.93 (3H, s), 2.43 (3H, s), 2.83 (3H, s), 3.14 (2H, m), 3.47 (2H, t), 4.03 (2H, dd), 4.36 (2H, s), 5.61 (1H, s), 5.89 (1H, s), 7.82 (1H, s), 7.93 (1H, s)
실시예 103: 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 103: 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol- Preparation of 5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000224
Figure PCTKR2022002310-appb-img-000224
실시예 102와 실질적으로 동일한 방법으로 실시예 93에서 제조한 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온을 사용하여 표제 화합물을 제조하였다(수득률: 44 %). 1H-NMR (400MHz, DMSO-d6) δ 1.30 (2H, m), 1.91 (3H, s), 2.46 (3H, s), 2.91 (2H, m), 3.85 (2H, m), 4.35 (2H, s), 5.44 (1H, m), 5.57 (1H, s), 7.42 (1H, br s), 7.92 (1H, s), 8.54 (1H, br s)5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8- prepared in Example 93 in substantially the same manner as in Example 102 The title compound was prepared using (tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (yield: 44%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30 (2H, m), 1.91 (3H, s), 2.46 (3H, s), 2.91 (2H, m), 3.85 (2H, m), 4.35 ( 2H, s), 5.44 (1H, m), 5.57 (1H, s), 7.42 (1H, br s), 7.92 (1H, s), 8.54 (1H, br s)
실시예 104: 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 104: 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydro pyrido[2,3-d]pyrimidin-7(6H)-one {2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran Preparation of -4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000225
Figure PCTKR2022002310-appb-img-000225
실시예 102와 실질적으로 동일한 방법으로 실시예 97에서 제조한 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온을 사용하여 표제의 화합물을 제조하였다(수득률: 45 %). 1H-NMR (400MHz, CDCl3) δ 1.10 (3H, t), 1.46 (2H, d), 2.23-2.35 (5H, m), 2.97 (2H, m), 3.37 (2H, t), 3.99 (2H, m), 4.40 (2H, s), 5.48 (1H, m), 5.85 (1H, s), 7.37 (1H, s), 8.36 (1H, m)2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-) prepared in Example 97 in substantially the same manner as in Example 102 The title compound was prepared using 4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (yield: 45%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.10 (3H, t), 1.46 (2H, d), 2.23-2.35 (5H, m), 2.97 (2H, m), 3.37 (2H, t), 3.99 ( 2H, m), 4.40 (2H, s), 5.48 (1H, m), 5.85 (1H, s), 7.37 (1H, s), 8.36 (1H, m)
실시예 105: 4-메틸-5-((5-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜린아미드 {4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)picolinamide}의 제조Example 105: 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)picolinamide {4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2] Preparation of ,3-d]pyrimidin-2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000226
Figure PCTKR2022002310-appb-img-000226
Figure PCTKR2022002310-appb-img-000227
Figure PCTKR2022002310-appb-img-000227
상기 반응식에서 실시예 1과 실질적으로 동일한 방법으로 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온과 5-아미노-4-메틸피콜리노니트릴을 사용하여 수득한 4-메틸-5-((5-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜리노니트릴 20 mg 및 2N-수산화나트륨 수용액 0.5 mL을 IPA 0.5 mL에 투입한 후, 70 ℃에서 3 시간 동안 교반하였다. 반응물을 상온으로 냉각시키고 농축한 후 Prep-HPLC로 정제하여 표제의 화합물을 수득하였다(수득률: 21 %). 1H-NMR (400MHz, CDCl3) δ 1.53 (2H, d), 2.40 (3H, s), 2.44 (3H, s), 3.00 (2H, m), 3.52 (2H, t), 4.09 (2H, dd), 5.55 (2H, m), 6.32 (1H, s), 7.19 (1H, s), 7.81 (1H, s), 8.11 (1H, s), 8.66 (1H, s), 9.20 (1H, s)2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidine-7 (8H) in substantially the same manner as in Example 1 in the above scheme 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7 obtained using -one and 5-amino-4-methylpicolinonitrile 20 mg of ,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)picolinonitrile and 0.5 mL of 2N-sodium hydroxide aqueous solution were added to 0.5 mL of IPA, and then at 70 °C for 3 hours stirred for a while. The reaction product was cooled to room temperature, concentrated, and purified by Prep-HPLC to obtain the title compound (yield: 21 %). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.53 (2H, d), 2.40 (3H, s), 2.44 (3H, s), 3.00 (2H, m), 3.52 (2H, t), 4.09 (2H, dd), 5.55 (2H, m), 6.32 (1H, s), 7.19 (1H, s), 7.81 (1H, s), 8.11 (1H, s), 8.66 (1H, s), 9.20 (1H, s) )
실시예 106: 4-메틸-5-((6-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜린아미드 {4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)picolinamide}의 제조Example 106: 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)picolinamide {4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2] Preparation of ,3-d]pyrimidin-2-yl)amino)picolinamide}
Figure PCTKR2022002310-appb-img-000228
Figure PCTKR2022002310-appb-img-000228
실시예 105와 실질적으로 동일한 방법으로 제조예 27에서 제조한 2-클로로-6-메틸-8-테트라하히드로피란-4-일-피리도[2,3-d]피리미딘-7(8H)-온을 사용하여 표제 화합물을 제조하였다(수득률: 20 %). 1H-NMR (400MHz, CD3OD) δ 1.50 (2H, d), 2.12 (3H, s), 2.42 (3H, s), 2.92 (2H, m), 3.43 (2H, t), 4.01 (2H, dd), 5.59 (1H, t), 7.62 (1H, s), 8.03 (1H, s), 8.61 (1H, s), 8.87 (1H, s)2-chloro-6-methyl-8-tetrahahydropyran-4-yl-pyrido[2,3-d]pyrimidine-7(8H) prepared in Preparation Example 27 in substantially the same manner as in Example 105 -On was used to prepare the title compound (yield: 20%). 1 H-NMR (400 MHz, CD 3 OD) δ 1.50 (2H, d), 2.12 (3H, s), 2.42 (3H, s), 2.92 (2H, m), 3.43 (2H, t), 4.01 (2H) , dd), 5.59 (1H, t), 7.62 (1H, s), 8.03 (1H, s), 8.61 (1H, s), 8.87 (1H, s)
실시예 107: 8-((1R,4R)-4-히드록시사이클로헥실)-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온 {8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 107: 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine -6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one {8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7- Preparation of methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000229
Figure PCTKR2022002310-appb-img-000229
Figure PCTKR2022002310-appb-img-000230
Figure PCTKR2022002310-appb-img-000230
실시예 101에서 제조한 (1R,4R)-4-(5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)-7-옥소피리도[2,3-d]피리미딘-8(7H)-일)사이클로헥실아세테이트 2.8 mg, 포타슘카보네이트 1.7 mg을 반응기에 넣고 메탄올 0.4 mL, 정제수 0.1 mL을 주입하였다. 상온에서 16 시간 동안 교반한 후 농축하였다. EtOH로 여과하고 여액을 농축하여 목적 화합물을 수득하였다(수득률: 55 %). 1H-NMR (400MHz, CD3OD) δ 1.28 (2H, m), 1.49 (2H, br s), 1.89 (5H, s), 2.42 (3H, s), 2.46 (2H, s), 6.24 (1H, s), 7.73 (1H, s), 8.38 (1H, s), 8.78 (1H, s), 9.00 (1H, br s)(1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino prepared in Example 101 )-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate 2.8 mg and potassium carbonate 1.7 mg were placed in a reactor, and 0.4 mL of methanol and 0.1 mL of purified water were injected. After stirring at room temperature for 16 hours, the mixture was concentrated. It was filtered with EtOH and the filtrate was concentrated to obtain the target compound (yield: 55 %). 1 H-NMR (400 MHz, CD 3 OD) δ 1.28 (2H, m), 1.49 (2H, br s), 1.89 (5H, s), 2.42 (3H, s), 2.46 (2H, s), 6.24 ( 1H, s), 7.73 (1H, s), 8.38 (1H, s), 8.78 (1H, s), 9.00 (1H, br s)
실시예 108: 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 108: 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine- 7(8H)-one {2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H )-one} preparation
Figure PCTKR2022002310-appb-img-000231
Figure PCTKR2022002310-appb-img-000231
Figure PCTKR2022002310-appb-img-000232
Figure PCTKR2022002310-appb-img-000232
2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 50 mg, 2-(3,4-디메톡시페닐)에탄-1-아민 97 mg 및 디이소프로필에틸아민 0.16 mL을 테트라하이드로푸란 2 mL에 넣고, 70 ℃에서 40 분 동안 교반하였다. 반응물을 농축하고 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 30 %). 1H-NMR (400MHz, CDCl3) δ 1.55 (2H, d), 2.33 (3H, s), 2.91 (2H, t), 3.16 (2H, s), 3.55 (2H, t), 3.77 (2H, q), 3.87 (6H, s), 4.11 (2H, d), 6.21 (1H, s), 6.67 (1H, s), 6.81 (2H, s), 8.48 (1H, br s)2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one 50 mg, 2- (3,4- 97 mg of dimethoxyphenyl)ethan-1-amine and 0.16 mL of diisopropylethylamine were added to 2 mL of tetrahydrofuran, and the mixture was stirred at 70° C. for 40 minutes. The reaction was concentrated and purified by Prep-HPLC to obtain the desired compound (yield: 30 %). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.55 (2H, d), 2.33 (3H, s), 2.91 (2H, t), 3.16 (2H, s), 3.55 (2H, t), 3.77 (2H, q), 3.87 (6H, s), 4.11 (2H, d), 6.21 (1H, s), 6.67 (1H, s), 6.81 (2H, s), 8.48 (1H, br s)
<실시예 109 및 실시예 110><Example 109 and Example 110>
실시예 109 및 실시예 110에서는 실시예 108과 실질적으로 동일한 방법으로 적절한 제조예의 화합물과 적절한 아민 유도체를 사용하여 제조하였다.Examples 109 and 110 were prepared in substantially the same manner as in Example 108, using the appropriate compounds and appropriate amine derivatives.
실시예 109: 2-((2-(6-메톡시피리딘-3-일)에틸)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온 {2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one}의 제조Example 109: 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one {2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, Preparation of 9-dihydro-8H-purin-8-one}
Figure PCTKR2022002310-appb-img-000233
Figure PCTKR2022002310-appb-img-000233
수득률: 55 %; 1H-NMR (400MHz, CDCl3) δ 1.67 (2H, d), 2.70 (2H, qd), 2.83 (2H, t), 3.35 (3H, s), 3.48 (2H, t), 3.61 (2H, q), 3.91 (3H, s), 4.10 (2H, dd), 4.48 (1H, tt), 4.91 (1H, t), 6.71 (1H, d), 7.48 (1H, dd), 7.75 (1H, s), 8.01 (1H, d)Yield: 55%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.67 (2H, d), 2.70 (2H, qd), 2.83 (2H, t), 3.35 (3H, s), 3.48 (2H, t), 3.61 (2H, q), 3.91 (3H, s), 4.10 (2H, dd), 4.48 (1H, tt), 4.91 (1H, t), 6.71 (1H, d), 7.48 (1H, dd), 7.75 (1H, s) ), 8.01 (1H, d)
실시예 110: 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 110: 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one {2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, Preparation of 3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000234
Figure PCTKR2022002310-appb-img-000234
수득률: 30 %; 1H-NMR (400MHz, CDCl3) δ 1.36 (2H, d), 1.56 (2H, s), 2.32 (3H, s), 2.99 (1H, m), 3.17 (2H, s), 3.54 (3H, m), 3.86 (6H, s), 4.10 (2H, m), 6.20 (1H, s), 6.74 (1H, s), 6.80 (2H, m), 8.44 (1H, s)Yield: 30%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36 (2H, d), 1.56 (2H, s), 2.32 (3H, s), 2.99 (1H, m), 3.17 (2H, s), 3.54 (3H, m), 3.86 (6H, s), 4.10 (2H, m), 6.20 (1H, s), 6.74 (1H, s), 6.80 (2H, m), 8.44 (1H, s)
실시예 111: 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 111: 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2, 3-d]pyrimidin-7(6H)-one {2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido Preparation of [2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000235
Figure PCTKR2022002310-appb-img-000235
실시예 108에서 얻은 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온을 사용하여 실시예 102와 실질적으로 동일한 방법으로 표제 화합물을 제조하였다(수득률: 42 %). 1H-NMR (400MHz, CD3OD) δ 1.45 (2H, d), 1.97 (3H, s), 2.82 (2H, t), 3.27 (2H, t), 3.57 (2H, m), 3.79 (3H, s), 3.82 (3H, s), 4.02 (2H, d), 4.24 (2H, s), 5.73 (1H, s), 6.80-6.89 (3H, m)2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine obtained in Example 108 The title compound was prepared in substantially the same manner as in Example 102 using -7(8H)-one (yield: 42%). 1 H-NMR (400 MHz, CD 3 OD) δ 1.45 (2H, d), 1.97 (3H, s), 2.82 (2H, t), 3.27 (2H, t), 3.57 (2H, m), 3.79 (3H) , s), 3.82 (3H, s), 4.02 (2H, d), 4.24 (2H, s), 5.73 (1H, s), 6.80-6.89 (3H, m)
실시예 112: 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 112: 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyri Do[2,3-d]pyrimidin-7(6H)-one {2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4 Preparation of -yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000236
Figure PCTKR2022002310-appb-img-000236
실시예 110에서 얻은 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온을 사용하여 실시예 102와 실질적으로 동일한 방법으로 표제 화합물을 제조하였다(수득률: 36 %). 1H-NMR (400MHz, CDCl3) δ 2.95 (1H, m), 3.16-3.27 (3H, m), 3.49 (2H, m), 3.84 (3H, s), 3.86 (3H, s), 4.04 (2H, dd), 4.26 (2H, s), 5.65 (2H, m), 6.73-6.78 (3H, m)Example 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d] obtained from 110 The title compound was prepared in substantially the same manner as in Example 102 using pyrimidin-7(8H)-one (yield: 36%). 1 H-NMR (400 MHz, CDCl 3 ) δ 2.95 (1H, m), 3.16-3.27 (3H, m), 3.49 (2H, m), 3.84 (3H, s), 3.86 (3H, s), 4.04 (2H, dd), 4.26 (2H, s), 5.65 (2H, m), 6.73-6.78 (3H, m)
실시예 113: 5-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 113: 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4 -yl)pyrido[2,3-d]pyrimidin-7(8H)-one {5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl Preparation of )amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000237
Figure PCTKR2022002310-appb-img-000237
단계 1: 4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-아민 {4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine}의 제조Step 1: Preparation of 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine {4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine}
Figure PCTKR2022002310-appb-img-000238
Figure PCTKR2022002310-appb-img-000238
실시예 34와 실질적으로 동일한 방법으로 표제 화합물을 제조하였다. Example 34 and substantially same in a way The title compound was prepared.
단계 2: 5-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Step 2: 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one {5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl) Preparation of amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000239
Figure PCTKR2022002310-appb-img-000239
단계 1에서 제조한 4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-아민 40 mg 및 2M 아이소프로필마그네슘클로라이드(in THF) 0.1 mL을 테트라하이드로푸란 2 mL에 넣고, 상온에서 40 분 동안 교반 후 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 50 mg 및 2M 아이소프로필마그네슘클로라이드 (in THF) 0.1 mL을 더 넣고, 60 ℃에서 16 시간 동안 교반하였다. 반응물에 에틸아세테이트 10 mL, 정제수 10 mL을 주입한 후, 에틸아세테이트 층을 분리하였다. 마그네슘설페이트 처리하여 여과하고 농축하여 얻은 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 17 %). 1H-NMR (400MHz, CDCl3) δ 1.53 (2H, d), 2.38 (3H, s), 2.42 (3H, s), 2.54 (3H, s), 2.97 (2H, qd), 3.36 (2H, t), 4.05 (2H, dd), 5.51 (1H, tt), 6.29 (1H, s), 6.99 (1H, s), 7.37 (1H, s), 7.55 (1H, s), 8.63 (1H, s), 9.01 (1H, s)4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine 40 prepared in step 1 mg and 2M isopropyl magnesium chloride (in THF) 0.1 mL tetrahydrofuran 2 into mL, at room temperature for 40 minutes agitation after 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 50 mg and 2M Isopropyl Magnesium Chloride (in THF) 0.1 mL add more, at 60 ℃ for 16 hours stirred. After adding 10 mL of ethyl acetate and 10 mL of purified water to the reaction mixture, the ethyl acetate layer was separated. The residue obtained by treatment with magnesium sulfate, filtration, and concentration By Prep-HPLC by purification target compound was obtained (yield: 17%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.53 (2H, d), 2.38 (3H, s), 2.42 (3H, s), 2.54 (3H, s), 2.97 (2H, qd), 3.36 (2H, t), 4.05 (2H, dd), 5.51 (1H, tt), 6.29 (1H, s), 6.99 (1H, s), 7.37 (1H, s), 7.55 (1H, s), 8.63 (1H, s), 9.01 (1H, s)
실시예 114: 5-메틸-2-((2-메틸-4-(1-메틸-1H-피라졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Example 114: 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl ) pyrido [2,3-d] pyrimidin-7 (8H) -one {5-methyl-2-((2-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino Preparation of )-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000240
Figure PCTKR2022002310-appb-img-000240
실시예 113과 실질적으로 동일한 방법으로 적절한 아닐린 유도체와 보론산 유도체를 사용하여 표제 화합물을 제조하였다(수득률: 22 %). 1H-NMR (400MHz, CDCl3) δ 1.51 (2H, d), 2.37 (6H, s), 3.07 (2H, qd), 3.49 (2H, t), 3.95 (3H, s), 4.07 (2H, dd), 5.58 (1H, tt), 6.26 (1H, s), 7.04 (1H, s), 7.37 (1H, s), 7.61 (1H, s), 7.75 (1H, s), 7.92 (1H, d), 8.61 (1H, s)Example 113 and practically The title compound was prepared in the same manner using appropriate aniline derivatives and boronic acid derivatives (yield: 22%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.51 (2H, d), 2.37 (6H, s), 3.07 (2H, qd), 3.49 (2H, t), 3.95 (3H, s), 4.07 (2H, dd), 5.58 (1H, tt), 6.26 (1H, s), 7.04 (1H, s), 7.37 (1H, s), 7.61 (1H, s), 7.75 (1H, s), 7.92 (1H, d), 8.61 (1H, s)
실시예 115: 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 115: 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000241
Figure PCTKR2022002310-appb-img-000241
단계 1: 6-(푸란-3-일)-4-메틸피리딘-3-아민 {6-(furan-3-yl)-4-methylpyridin-3-amine}의 제조Step 1: Preparation of 6-(furan-3-yl)-4-methylpyridin-3-amine {6-(furan-3-yl)-4-methylpyridin-3-amine}
Figure PCTKR2022002310-appb-img-000242
Figure PCTKR2022002310-appb-img-000242
실시예 34의 단계 1과 실질적으로 동일한 방법으로 적절한 유도체를 사용하여 표제 화합물을 제조하였다.Example Step 1 of 34 realistically same in a way appropriate derivatives using The title compound was prepared.
단계 2: 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라히드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온 {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}의 제조Step 2: 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ 2,3-d]pyrimidin-7(8H)-one {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro- Preparation of 2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one}
Figure PCTKR2022002310-appb-img-000243
Figure PCTKR2022002310-appb-img-000243
실시예 113의 단계 2와 실질적으로 동일한 방법으로 표제 화합물을 제조하였다.Example Step 2 of 113 and substantially The title compound was prepared in the same manner.
단계 3: 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Step 3: 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one {2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000244
Figure PCTKR2022002310-appb-img-000244
실시예 102의 단계 2와 실질적으로 동일한 방법으로 표제 화합물을 제조하였다(수득률: 11 %). 1H-NMR (400MHz, CDCl3) δ 1.93 (3H, s), 2.38 (3H, s), 3.10 (2H, m), 3.48 (2H, m), 4.02 (2H, dd), 4.35 (2H, s), 5.57 (1H, m), 5.93 (1H, s), 6.34 (1H, s), 6.87 (1H, s), 7.40 (1H, s), 7.51 (1H, s), 8.02 (1H, s), 8.46 (1H, s)Example Step 2 of 102 and substantially The title compound was prepared in the same manner (yield: 11%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.93 (3H, s), 2.38 (3H, s), 3.10 (2H, m), 3.48 (2H, m), 4.02 (2H, dd), 4.35 (2H, s), 5.57 (1H, m), 5.93 (1H, s), 6.34 (1H, s), 6.87 (1H, s), 7.40 (1H, s), 7.51 (1H, s), 8.02 (1H, s), 8.46 (1H, s)
<실시예 116 및 실시예 117><Examples 116 and 117>
실시예 116 및 실시예 117에서는 실시예 115와 실질적으로 동일한 방법으로 적절한 중간체, 아민 유도체 및 보론산 유도체를 사용하여 제조하였다.Examples 116 and 117 were prepared in substantially the same manner as in Example 115 using appropriate intermediates, amine derivatives and boronic acid derivatives.
실시예 116: 2-((6-(푸란-2-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 116: 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one {2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000245
Figure PCTKR2022002310-appb-img-000245
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 1.93 (3H, s), 2.39 (3H, s), 3.10 (2H, m), 3.50 (2H, m), 4.02 (2H, m), 4.36 (2H, s), 5.93 (1H, s), 6.36 (1H, s), 6.55 (1H, m), 7.05 (1H, d), 7.54 (1H, s), 7.63 (1H, s), 8.47 (1H, s)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.93 (3H, s), 2.39 (3H, s), 3.10 (2H, m), 3.50 (2H, m), 4.02 (2H, m), 4.36 (2H, s), 5.93 (1H, s), 6.36 (1H, s), 6.55 (1H, m), 7.05 (1H, d), 7.54 (1H, s), 7.63 (1H, s), 8.47 (1H, s)
실시예 117: 5-에틸-2-((4-메틸-6-(티오펜-3-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온 {5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}의 제조Example 117: 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one {5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3- Preparation of yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one}
Figure PCTKR2022002310-appb-img-000246
Figure PCTKR2022002310-appb-img-000246
수득률: 10 %; 1H-NMR (400MHz, CD3OD) δ 1.12 (3H, t), 1.31 (2H, m), 2.33-2.38 (5H, m), 2.85 (2H, m), 3.81 (2H, m), 4.39 (2H, s), 5.43 (1H, s), 5.81 (1H, s), 7.51 (1H, dd), 7.67 (1H, d), 7.74 (1H, s), 7.96 (1H, d), 8.44 (1H, br s)Yield: 10%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.12 (3H, t), 1.31 (2H, m), 2.33-2.38 (5H, m), 2.85 (2H, m), 3.81 (2H, m), 4.39 (2H, s), 5.43 (1H, s), 5.81 (1H, s), 7.51 (1H, dd), 7.67 (1H, d), 7.74 (1H, s), 7.96 (1H, d), 8.44 (1H, br s)
실시예 118: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 118: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8- Dihydropteridine-6,7-dione {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl) Preparation of -5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000247
Figure PCTKR2022002310-appb-img-000247
Figure PCTKR2022002310-appb-img-000248
Figure PCTKR2022002310-appb-img-000248
제조예 15에서 제조한 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 30 mg, Brettphos Pd G3 10 mg, 2,5-디메틸벤조[d]티아졸-6-아민 28 mg 및 세슘카보네이트 91 mg을 다이옥산 1.5 mL에 넣고 160 ℃에서 30 분간 반응하였다. 반응물을 상온으로 냉각시키고, 에틸아세테이트 10 mL 및 정제수 10 mL을 주입하였다. 에틸아세테이트 층을 분리하고 소듐설페이트 처리한 후, 여과하여 얻은 용액을 농축한 잔사물을 Prep HPLC로 정제하여 목적 화합물을 제조하였다(수득률: 20 %). 1H-NMR (400MHz, CDCl3) δ 1.58-1.62 (2H, m), 2.49 (3H, s), 2.83 (3H, s), 2.92-3.02 (2H, m), 3.47-3.53 (2H, m), 3.62 (3H, s), 4.10-4.14 (2H, m), 5.39-5.47 (1H, m), 7.04-8.45 (4H, m)2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione 30 mg prepared in Preparation Example 15, Brettphos Pd G 3 10 mg, 28 mg of 2,5-dimethylbenzo[d]thiazol-6-amine and 91 mg of cesium carbonate were added to 1.5 mL of dioxane and reacted at 160° C. for 30 minutes. The reaction was cooled to room temperature, and 10 mL of ethyl acetate and 10 mL of purified water were injected. The ethyl acetate layer was separated, treated with sodium sulfate, filtered, and the concentrated residue was purified by Prep HPLC to prepare the target compound (yield: 20%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.58-1.62 (2H, m), 2.49 (3H, s), 2.83 (3H, s), 2.92-3.02 (2H, m), 3.47-3.53 (2H, m) ), 3.62 (3H, s), 4.10-4.14 (2H, m), 5.39-5.47 (1H, m), 7.04-8.45 (4H, m)
<실시예 119 내지 실시예 148><Examples 119 to 148>
실시예 119 내지 실시예 148 에서는 실시예 118과 실질적으로 동일한 방법으로 적절한 중간체와 아민 유도체를 사용하여 제조하였다.Examples 119 to 148 were prepared in substantially the same manner as in Example 118, using appropriate intermediates and amine derivatives.
실시예 119: 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 119: 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8- Preparation of (tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000249
Figure PCTKR2022002310-appb-img-000249
수득률: 20 %; 1H-NMR (400MHz, CDCl3) δ 1.65-1.69 (2H, m), 2.61 (3H, s), 3.63-3.69 (5H, m), 4.13-4.17 (2H, m), 5.52-5.60 (1H, m), 7.23-8.84 (4H, m)Yield: 20%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.65-1.69 (2H, m), 2.61 (3H, s), 3.63-3.69 (5H, m), 4.13-4.17 (2H, m), 5.52-5.60 (1H, m), 7.23-8.84 (4H, m)
실시예 120: 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 120: 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropteridine-6,7-dione {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H- Preparation of pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000250
Figure PCTKR2022002310-appb-img-000250
수득률: 13 %; 1H-NMR (400MHz, CDCl3) δ 1.53-1.56 (2H, m), 2.23 (3H, s), 2.82-2.92 (2H, m), 3.43-3.49 (2H, m), 3.59 (3H, s), 4.04-4.08 (2H, m), 5.32-5.40 (1H, m), 5.96 (2H, s), 6.64-8.21 (5H, m)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.53-1.56 (2H, m), 2.23 (3H, s), 2.82-2.92 (2H, m), 3.43-3.49 (2H, m), 3.59 (3H, s), 4.04-4.08 (2H, m), 5.32-5.40 (1H, m), 5.96 (2H, s), 6.64-8.21 (5H, m)
실시예 121: 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 121: 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-5,8-dihydropteridine-6,7-dione {5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6) Preparation of -yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000251
Figure PCTKR2022002310-appb-img-000251
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 1.68-1.72 (2H, m), 2.21 (3H, s), 2.84-2.93 (2H, m), 3.48-3.54 (2H, m), 3.59 (3H, s), 4.24-4.26 (5H, m), 5.36-5.44 (1H, m), 6.67-8.21 (4H, m)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.68-1.72 (2H, m), 2.21 (3H, s), 2.84-2.93 (2H, m), 3.48-3.54 (2H, m), 3.59 (3H, s), 4.24-4.26 (5H, m), 5.36-5.44 (1H, m), 6.67-8.21 (4H, m)
실시예 122: 5-메틸-2-((2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 122: 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione {5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000252
Figure PCTKR2022002310-appb-img-000252
수득률: 16 %; 1H-NMR (400MHz, CD3OD) δ 1.58-1.61 (2H, m), 2.37 (3H, s), 2.86-2.97 (2H, m), 3.43-3.49 (2H, m), 3.61 (3H, s), 3.96 (3H, s), 4.07-4.11 (3H, m), 7.35-8.29 (6H, m)Yield: 16%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.58-1.61 (2H, m), 2.37 (3H, s), 2.86-2.97 (2H, m), 3.43-3.49 (2H, m), 3.61 (3H, s), 3.96 (3H, s), 4.07-4.11 (3H, m), 7.35-8.29 (6H, m)
실시예 123: 5-메틸-2-((2-메틸-4-(1-메틸-1H-피라졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 123: 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione {5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000253
Figure PCTKR2022002310-appb-img-000253
수득률: 15 %; 1H-NMR (400MHz, CDCl3) δ 1.57-1.61 (2H, m), 2.37 (3H, s), 2.91-3.01 (2H, m), 3.46-3.51 (2H, m), 3.61 (3H, s), 3.96 (3H, s), 4.09-4.13 (2H, m), 5.38-5.46 (1H, m), 6.86-8.24 (6H, m)Yield: 15%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.57-1.61 (2H, m), 2.37 (3H, s), 2.91-3.01 (2H, m), 3.46-3.51 (2H, m), 3.61 (3H, s), 3.96 (3H, s), 4.09-4.13 (2H, m), 5.38-5.46 (1H, m), 6.86-8.24 (6H, m)
실시예 124: 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 124: 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6 ,7-dione {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione} manufacture of
Figure PCTKR2022002310-appb-img-000254
Figure PCTKR2022002310-appb-img-000254
수득률: 8 %; 1H-NMR (400MHz, CDCl3) δ 1.62-1.66 (2H, m), 2.60 (3H, s), 2.98-3.08 (2H, m), 3.48-3.54 (2H, m), 3.65 (3H, s), 4.11-4.15 (2H, m), 5.44-5.52 (1H, m), 7.18-8.83 (7H, m)Yield: 8 %; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.62-1.66 (2H, m), 2.60 (3H, s), 2.98-3.08 (2H, m), 3.48-3.54 (2H, m), 3.65 (3H, s), 4.11-4.15 (2H, m), 5.44-5.52 (1H, m), 7.18-8.83 (7H, m)
실시예 125: 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}의 제조Example 125: 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-((tetrahydro-2H- Pyran-4-yl)methyl)-5,8-dihydropteridin-6,7-dione {5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4] Preparation of dioxin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000255
Figure PCTKR2022002310-appb-img-000255
수득률: 13 %; 1H-NMR (400MHz, CD3OD) δ 1.41-1.51 (4H, m), 2.21 (3H, s), 3.29-3.36 (2H, m), 3.63 (3H, s), 3.91-3.94 (2H, m), 4.12-4.14 (2H, m), 4.22-4.27 (5H, m), 6.76-8.26 (3H, m)Yield: 13%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.41-1.51 (4H, m), 2.21 (3H, s), 3.29-3.36 (2H, m), 3.63 (3H, s), 3.91-3.94 (2H, m), 4.12-4.14 (2H, m), 4.22-4.27 (5H, m), 6.76-8.26 (3H, m)
실시예 126: 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}의 제조Example 126: 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl )-5,8-dihydropteridine-6,7-dione {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000256
Figure PCTKR2022002310-appb-img-000256
수득률: 15 %; 1H-NMR (400MHz, CD3OD) δ 1.39-1.13 (4H, m), 1.49-1.57 (2H, m), 2.22 (3H, s), 3.27-3.36 (2H, m), 3.63 (3H, s), 3.91-3.99 (4H, m), 5.95 (2H, s), 6.75-8.26 (3H, m)Yield: 15%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.39-1.13 (4H, m), 1.49-1.57 (2H, m), 2.22 (3H, s), 3.27-3.36 (2H, m), 3.63 (3H, s), 3.91-3.99 (4H, m), 5.95 (2H, s), 6.75-8.26 (3H, m)
실시예 127: 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}의 제조Example 127: 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-((tetrahydro-2H-pyran-4- yl)methyl)-5,8-dihydropteridine-6,7-dione {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino) Preparation of -8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000257
Figure PCTKR2022002310-appb-img-000257
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 1.54-1.64 (2H, m), 1.69-1.71 (2H, m), 2.27-2.36 (1H, m), 2.61 (3H, s), 3.27-3.33 (2H, m), 3.69 (3H, s), 3.95-3.98 (2H, m), 4.38-4.39 (2H, m), 7.28-8.91 (4H, m)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.54-1.64 (2H, m), 1.69-1.71 (2H, m), 2.27-2.36 (1H, m), 2.61 (3H, s), 3.27-3.33 (2H, m), 3.69 (3H, s), 3.95-3.98 (2H, m), 4.38-4.39 (2H, m), 7.28-8.91 (4H, m)
실시예 128: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}의 제조Example 128: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-5 ,8-dihydropteridine-6,7-dione {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran- Preparation of 4-yl)methyl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000258
Figure PCTKR2022002310-appb-img-000258
수득률: 23 %; 1H-NMR (400MHz, CDCl3) δ 1.44-1.50 (4H, m), 2.11-2.17 (1H, m), 2.48 (3H, s), 2.75-2.83 (3H, s), 3.22-3.28 (2H, m), 3.64 (3H, s), 3.90-3.95 (2H, m), 4.20-4.22 (2H, m), 6.99-8.43 (4H, m)Yield: 23%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.44-1.50 (4H, m), 2.11-2.17 (1H, m), 2.48 (3H, s), 2.75-2.83 (3H, s), 3.22-3.28 (2H, m), 3.64 (3H, s), 3.90-3.95 (2H, m), 4.20-4.22 (2H, m), 6.99-8.43 (4H, m)
실시예 129: 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione}의 제조Example 129: 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteri Din-6,7-dione {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine- Preparation of 6,7-dione}
Figure PCTKR2022002310-appb-img-000259
Figure PCTKR2022002310-appb-img-000259
수득률: 10 %; 1H-NMR (400MHz, CDCl3) δ 1.44-1.50 (4H, m), 2.13-2.21 (1H, m), 2.59 (3H, s), 3.19-3.26 (2H, m), 3.66 (3H, s), 3.87-3.92 (2H, m), 4.26-4.28 (2H, m), 7.14-8.83 (7H, m)Yield: 10%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.44-1.50 (4H, m), 2.13-2.21 (1H, m), 2.59 (3H, s), 3.19-3.26 (2H, m), 3.66 (3H, s), 3.87-3.92 (2H, m), 4.26-4.28 (2H, m), 7.14-8.83 (7H, m)
실시예 130: 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 130: 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5, 8-dihydropteridine-6,7-dione {8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino Preparation of )-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000260
Figure PCTKR2022002310-appb-img-000260
수득률: 16 %; 1H-NMR (400MHz, CDCl3) δ 1.68-1.71 (2H, m), 1.78-1.93 (2H, m), 2.17-2.24 (5H, m), 2.80-2.89 (2H, m), 3.59 (3H, s), 5.17-5.23 (1H, m), 5.96 (2H, s), 6.59-8.21 (4H, m)Yield: 16%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.68-1.71 (2H, m), 1.78-1.93 (2H, m), 2.17-2.24 (5H, m), 2.80-2.89 (2H, m), 3.59 (3H, s), 5.17-5.23 (1H, m), 5.96 (2H, s), 6.59-8.21 (4H, m)
실시예 131: 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 131: 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6- yl)amino)-5,8-dihydropteridine-6,7-dione {8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b Preparation of ][1,4]dioxin-6-yl)amino)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000261
Figure PCTKR2022002310-appb-img-000261
수득률: 15 %; 1H-NMR (400MHz, CDCl3) δ 1.68-1.72 (2H, m), 1.90-1.91 (2H, m), 2.20 (3H, s), 3.30 (3H, s), 3.56-3.62 (2H, m), 4.07-4.11 (4H, m), 4.23-4.25 (4H, m), 4.81-4.89 (1H, m), 6.43-7.62 (4H, m)Yield: 15%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.68-1.72 (2H, m), 1.90-1.91 (2H, m), 2.20 (3H, s), 3.30 (3H, s), 3.56-3.62 (2H, m), 4.07-4.11 (4H, m), 4.23-4.25 (4H, m), 4.81-4.89 (1H, m), 6.43-7.62 (4H, m)
실시예 132: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 132: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8- Dihydropteridin-6(5H)-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl Preparation of )-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000262
Figure PCTKR2022002310-appb-img-000262
수득률: 12 %; 1H-NMR (400MHz, CDCl3) δ 1.70-1.73 (2H, m), 1.84-1.94 (2H, m), 2.46 (3H, s), 2.81 (3H, s), 3.33 (3H, s), 3.53-3.71 (2H, m), 4.10-4.14 (4H, m), 4.83-4.91 (1H, m), 6.70-8.63 (4H, m)Yield: 12%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.70-1.73 (2H, m), 1.84-1.94 (2H, m), 2.46 (3H, s), 2.81 (3H, s), 3.33 (3H, s), 3.53-3.71 (2H, m), 4.10-4.14 (4H, m), 4.83-4.91 (1H, m), 6.70-8.63 (4H, m)
실시예 133: 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 133: 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)-7,8-dihydropteridin-6(5H)-one {5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a Preparation of ]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000263
Figure PCTKR2022002310-appb-img-000263
수득률: 13 %; 1H-NMR (400MHz, CD3OD) δ 1.73-1.76 (2H, m), 1.87-1.98 (2H, m), 2.52 (3H, s), 3.34 (3H, s), 3.62-3.68 (2H, m), 4.09-4.15 (2H, m), 4.81-4.89 (1H, m), 7.58-9.49 (4H, m)Yield: 13%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.73-1.76 (2H, m), 1.87-1.98 (2H, m), 2.52 (3H, s), 3.34 (3H, s), 3.62-3.68 (2H, m), 4.09-4.15 (2H, m), 4.81-4.89 (1H, m), 7.58-9.49 (4H, m)
실시예 134: 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 134: 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8- Dihydropteridin-6(5H)-one {2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl Preparation of )-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000264
Figure PCTKR2022002310-appb-img-000264
수득률: 13 %; 1H-NMR (400MHz, CDCl3) δ 1.70-1.74 (2H, m), 1.89-1.91 (2H, m), 2.43 (3H, s), 2.80 (3H, s), 3.32 (3H, s), 3.57-3.63 (2H, m), 4.06-4.09 (4H, m), 4.85-4.91 (1H, m), 6.66-8.63 (4H, m)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.70-1.74 (2H, m), 1.89-1.91 (2H, m), 2.43 (3H, s), 2.80 (3H, s), 3.32 (3H, s), 3.57-3.63 (2H, m), 4.06-4.09 (4H, m), 4.85-4.91 (1H, m), 6.66-8.63 (4H, m)
실시예 135: 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 135: 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-7,8-dihydropteridin-6(5H)-one {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000265
Figure PCTKR2022002310-appb-img-000265
수득률: 23 %; 1H-NMR (400MHz, CDCl3) δ 1.78-1.82 (2H, m), 1.87-1.97 (2H, m), 2.56 (3H, s), 3.36 (3H, s), 3.74-3.79 (2H, m), 4.13-4.17 (4H, m), 4.96-5.04 (1H, m), 6.95-8.86 (4H, m)Yield: 23%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.78-1.82 (2H, m), 1.87-1.97 (2H, m), 2.56 (3H, s), 3.36 (3H, s), 3.74-3.79 (2H, m), 4.13-4.17 (4H, m), 4.96-5.04 (1H, m), 6.95-8.86 (4H, m)
실시예 136: 2-((5-히드록시나프탈렌-2-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 136: 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine- 6(5H)-one {2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H) manufacture of -one}
Figure PCTKR2022002310-appb-img-000266
Figure PCTKR2022002310-appb-img-000266
수득률: 8 %; 1H-NMR (400MHz, CD3OD) δ 1.76-1.79 (2H, m), 1.88-1.98 (2H, m), 3.33 (3H, s), 3.59-3.65 (2H, m), 4.12-4.15 (4H, m), 4.93-5.00 (1H, m), 6.73-8.17 (7H, m)Yield: 8 %; 1 H-NMR (400 MHz, CD 3 OD) δ 1.76-1.79 (2H, m), 1.88-1.98 (2H, m), 3.33 (3H, s), 3.59-3.65 (2H, m), 4.12-4.15 (4H, m), 4.93-5.00 (1H, m), 6.73-8.17 (7H, m)
실시예 137: 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 137: 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7 ,8-dihydropteridin-6(5H)-one {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H Preparation of -pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000267
Figure PCTKR2022002310-appb-img-000267
수득률: 6 %; 1H-NMR (400MHz, CDCl3) δ 1.66-1.70 (2H, m), 1.80-1.90 (2H, m), 2.22 (3H, s), 3.30 (3H, s), 3.51-3.57 (2H, m), 4.07-4.11 (4H, m), 4.76-4.84 (1H, m), 5.92 (2H, s), 6.36-7.62 (4H, m)Yield: 6%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.66-1.70 (2H, m), 1.80-1.90 (2H, m), 2.22 (3H, s), 3.30 (3H, s), 3.51-3.57 (2H, m), 4.07-4.11 (4H, m), 4.76-4.84 (1H, m), 5.92 (2H, s), 6.36-7.62 (4H, m)
실시예 138: 5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 138: 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one {5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000268
Figure PCTKR2022002310-appb-img-000268
수득률: 7 %; 1H-NMR (400MHz, CDCl3) δ 1.65-1.69 (2H, m), 1.89-1.91 (2H, m), 2.34 (3H, s), 3.31 (3H, s), 3.50-3.56 (2H, m), 3.96 (3H, s), 4.06-4.10 (4H, m), 4.74-4.82 (1H, m), 6.41 (1H, s), 7.31-8.95 (5H, m)Yield: 7%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.65-1.69 (2H, m), 1.89-1.91 (2H, m), 2.34 (3H, s), 3.31 (3H, s), 3.50-3.56 (2H, m), 3.96 (3H, s), 4.06-4.10 (4H, m), 4.74-4.82 (1H, m), 6.41 (1H, s), 7.31-8.95 (5H, m)
실시예 139: 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 139: 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one {5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin- Preparation of 6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000269
Figure PCTKR2022002310-appb-img-000269
수득률: 8 %; 1H-NMR (400MHz, CDCl3) δ 1.67-1.72 (2H, m), 1.80-1.90 (2H, m), 2.21 (3H, s), 3.30 (3H, s), 3.56-3.62 (2H, m), 4.07-4.11 (4H, m), 4.23-4.25 (4H, m), 4.81-4.89 (1H, m), 6.41-7.62 (4H, m)Yield: 8 %; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.67-1.72 (2H, m), 1.80-1.90 (2H, m), 2.21 (3H, s), 3.30 (3H, s), 3.56-3.62 (2H, m), 4.07-4.11 (4H, m), 4.23-4.25 (4H, m), 4.81-4.89 (1H, m), 6.41-7.62 (4H, m)
실시예 140: 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 140: 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6 (5H)-one {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)- manufacture of one}
Figure PCTKR2022002310-appb-img-000270
Figure PCTKR2022002310-appb-img-000270
수득률: 6 %; 1H-NMR (400MHz, CDCl3) δ 1.72-1.76 (2H, m), 1.87-1.97 (2H, m), 2.57 (3H, s), 3.35 (3H, s), 3.53-3.58 (2H, m), 4.12-4.15 (4H, m), 4.90-4.98 (1H, m), 6.86-8.77 (7H, m)Yield: 6%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72-1.76 (2H, m), 1.87-1.97 (2H, m), 2.57 (3H, s), 3.35 (3H, s), 3.53-3.58 (2H, m), 4.12-4.15 (4H, m), 4.90-4.98 (1H, m), 6.86-8.77 (7H, m)
실시예 141: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-((테트라하이드로-2H-피란-4-일)메틸)-7,8-디하이드로프테리딘-6(5H)-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 141: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-7 ,8-dihydropteridin-6(5H)-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran) Preparation of -4-yl)methyl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000271
Figure PCTKR2022002310-appb-img-000271
수득률: 10 %; 1H-NMR (400MHz, CD3OD) δ 1.33-1.43 (2H, m), 1.60-1.63 (2H, m), 2.05-2.11 (1H, m), 2.46 (3H, s), 2.81 (3H, s), 3.33 (3H, s), 3.45-3.47 (2H, m), 3.95-4.06 (4H, m), 4.20 (2H, s), 7.63-8.50 (3H, m)Yield: 10%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.33-1.43 (2H, m), 1.60-1.63 (2H, m), 2.05-2.11 (1H, m), 2.46 (3H, s), 2.81 (3H, s), 3.33 (3H, s), 3.45-3.47 (2H, m), 3.95-4.06 (4H, m), 4.20 (2H, s), 7.63-8.50 (3H, m)
실시예 142: 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-7,8-디하이드로프테리딘-6(5H)-온 {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 142: 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteri Din-6(5H)-one {5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridin Preparation of -6(5H)-one}
Figure PCTKR2022002310-appb-img-000272
Figure PCTKR2022002310-appb-img-000272
수득률: 5 %; 1H-NMR (400MHz, CD3OD) δ 1.36-1.47 (2H, m), 1.60-1.63 (2H, m), 2.05-2.11 (1H, m), 2.57 (3H, s), 3.31-3.36 (2H, m), 3.54-3.56 (2H, m), 3.93-3.97 (2H, m), 4.22 (2H, s), 7.37-8.69 (6H, m)Yield: 5%; 1 H-NMR (400 MHz, CD 3 OD) δ 1.36-1.47 (2H, m), 1.60-1.63 (2H, m), 2.05-2.11 (1H, m), 2.57 (3H, s), 3.31-3.36 (2H, m), 3.54-3.56 (2H, m), 3.93-3.97 (2H, m), 4.22 (2H, s), 7.37-8.69 (6H, m)
실시예 143: 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5,7-디메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온 {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one}의 제조Example 143: 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran-4-yl)-7, 8-dihydropteridin-6(5H)-one {2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran Preparation of -4-yl)-7,8-dihydropteridin-6(5H)-one}
Figure PCTKR2022002310-appb-img-000273
Figure PCTKR2022002310-appb-img-000273
수득률: 8 %; 1H-NMR (400MHz, CDCl3) δ 1.36-1.38 (3H, m), 1.67-2.11 (4H, m), 2.46 (3H, s), 2.81 (3H, s), 3.49-3.59 (3H, m), 4.08-4.14 (2H, m), 4.32-4.37 (1H, m), 4.54-4.62 (1H, m), 6.73-8.64 (4H, m)Yield: 8 %; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.38 (3H, m), 1.67-2.11 (4H, m), 2.46 (3H, s), 2.81 (3H, s), 3.49-3.59 (3H, m), 4.08-4.14 (2H, m), 4.32-4.37 (1H, m), 4.54-4.62 (1H, m), 6.73-8.64 (4H, m)
실시예 144: 8-사이클로헥실-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 144: 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridin-6 ,7-dione {8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione} Produce
Figure PCTKR2022002310-appb-img-000274
Figure PCTKR2022002310-appb-img-000274
제조예 17에서 제조한 2-클로로-8-사이클로헥실-5-메틸-프테리딘-6,7-디온 29.7 mg, 6-메틸벤조[d][1,3]다이옥솔-5-아민 18.2 mg, Pd(dba)2 5.8 mg, BINAP 6.2 mg 및 세슘카보네이트 65.2 mg을 다이옥산 3 mL에 넣고, 120 ℃에서 12 시간 동안 교반하였다. 반응물을 냉각시킨 후, 셀라이트 여과하고 농축하여 얻은 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 15 %). 1H-NMR (400MHz, CDCl3) δ 1.13 (1H, m), 1.35 (2H, q), 1.61 (3H, m), 1.82 (2H, d), 2.22 (3H, s), 2.44 (2H, q), 3.58 (3H, s), 5.08 (1H, t), 5.95 (2H, s), 6.57 (1H, s), 6.74 (1H, s), 7.15 (1H, s), 8.18 (1H, s)2-chloro-8-cyclohexyl-5-methyl-pteridine-6,7-dione prepared in Preparation Example 17 29.7 mg, 6-methylbenzo [d] [1,3] dioxol-5-amine 18.2 mg, Pd(dba) 2 5.8 mg, BINAP 6.2 mg, and cesium carbonate 65.2 mg were placed in 3 mL of dioxane and stirred at 120° C. for 12 hours. After cooling the reaction, the residue obtained by filtration and concentration with Celite was purified by Prep-HPLC to obtain the target compound (yield: 15%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.13 (1H, m), 1.35 (2H, q), 1.61 (3H, m), 1.82 (2H, d), 2.22 (3H, s), 2.44 (2H, q), 3.58 (3H, s), 5.08 (1H, t), 5.95 (2H, s), 6.57 (1H, s), 6.74 (1H, s), 7.15 (1H, s), 8.18 (1H, s)
<실시예 145 내지 실시예 154><Examples 145 to 154>
실시예 145 내지 실시예 154 에서는 실시예 144와 실질적으로 동일한 방법으로 적절한 제조예의 화합물과 적절한 아민 유도체를 사용하여 제조하였다.Examples 145 to 154 were prepared in substantially the same manner as in Example 144, using the appropriate compounds and appropriate amine derivatives.
실시예 145: 8-사이클로헥실-5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 145: 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteri din-6,7-dione {8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6, Preparation of 7-dione}
Figure PCTKR2022002310-appb-img-000275
Figure PCTKR2022002310-appb-img-000275
수득률: 13 %; 1H-NMR (400MHz, CDCl3) δ 1.29 (1H, m), 1.51 (2H, d), 1.75 (3H, d), 1.92 (2H, d), 2.59 (2H, q), 2.60 (3H, s), 3.65 (3H, s), 5.29 (1H, t), 7.18 (1H, s), 7.85 (1H, s), 8.33 (1H, s), 8.85 (1H, s)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29 (1H, m), 1.51 (2H, d), 1.75 (3H, d), 1.92 (2H, d), 2.59 (2H, q), 2.60 (3H, s), 3.65 (3H, s), 5.29 (1H, t), 7.18 (1H, s), 7.85 (1H, s), 8.33 (1H, s), 8.85 (1H, s)
실시예 146: 8-사이클로헥실-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온 {8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione}의 제조Example 146: 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7- Preparation of dione {8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000276
Figure PCTKR2022002310-appb-img-000276
수득률: 11 %; 1H-NMR (400MHz, CDCl3) δ 1.36 (3H, q), 1.66 (3H, d), 1.85 (2H, d), 2.48 (3H, s), 2.49 (2H, q), 2.83 (3H, s), 3.62 (3H, s), 5.16 (1H, t), 6.95 (1H, s), 7.82 (1H, s), 8.25 (1H, s), 8.43 (1H, s)Yield: 11%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36 (3H, q), 1.66 (3H, d), 1.85 (2H, d), 2.48 (3H, s), 2.49 (2H, q), 2.83 (3H, s), 3.62 (3H, s), 5.16 (1H, t), 6.95 (1H, s), 7.82 (1H, s), 8.25 (1H, s), 8.43 (1H, s)
실시예 147: 8-사이클로헥실-5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 147: 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8- Dihydropteridine-6,7-dione {8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)- Preparation of 5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000277
Figure PCTKR2022002310-appb-img-000277
수득률: 15 %; 1H-NMR (400MHz, CDCl3) δ 1.12 (1H, s), 1.36 (3H, q), 1.80 (4H, d), 2.20 (3H, s), 2.42 (2H, q), 3.58 (3H, s), 4.25 (4H, s), 5.08 (1H, t), 6.76 (1H, s), 6.91 (1H, s), 7.18 (1H, s), 8.16 (1H, s)Yield: 15%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.12 (1H, s), 1.36 (3H, q), 1.80 (4H, d), 2.20 (3H, s), 2.42 (2H, q), 3.58 (3H, s), 4.25 (4H, s), 5.08 (1H, t), 6.76 (1H, s), 6.91 (1H, s), 7.18 (1H, s), 8.16 (1H, s)
실시예 148: 8-사이클로헥실-5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclohexyl-5-methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 148: 8-cyclohexyl-5-methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione {8-cyclohexyl-5 Preparation of -methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000278
Figure PCTKR2022002310-appb-img-000278
수득률: 15 %; 1H-NMR (400MHz, CDCl3) δ 1.34 (3H, q), 1.70 (3H, d), 1.85 (2H, d), 2.53 (2H, q), 2.59 (3H, q), 3.64 (3H, s), 5.22 (1H, t), 7.09 (1H, t), 7.37 (1H, q), 7.99 (1H, s), 8.10 (1H, d), 8.30 (1H, s), 8.43 (1H, s), 8.82 (1H, d)Yield: 15%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34 (3H, q), 1.70 (3H, d), 1.85 (2H, d), 2.53 (2H, q), 2.59 (3H, q), 3.64 (3H, s), 5.22 (1H, t), 7.09 (1H, t), 7.37 (1H, q), 7.99 (1H, s), 8.10 (1H, d), 8.30 (1H, s), 8.43 (1H, s), 8.82 (1H, d)
실시예 149: 8-사이클로펜틸-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 149: 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6 ,7-dione {8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione} Produce
Figure PCTKR2022002310-appb-img-000279
Figure PCTKR2022002310-appb-img-000279
수득률: 13 %; 1H-NMR (400MHz, CDCl3) δ 1.59 (2H, m), 1.87 (4H, m), 2.18 (2H, m), 2.22 (3H, s), 3.59 (3H, s), 5.61 (1H, q), 5.95 (2H, s), 6.54 (1H, s), 6.73 (1H, s), 7.15 (1H, s), 8.19 (1H, s)Yield: 13%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.59 (2H, m), 1.87 (4H, m), 2.18 (2H, m), 2.22 (3H, s), 3.59 (3H, s), 5.61 (1H, q), 5.95 (2H, s), 6.54 (1H, s), 6.73 (1H, s), 7.15 (1H, s), 8.19 (1H, s)
실시예 150: 8-사이클로펜틸-5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 150: 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteri din-6,7-dione {8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6, Preparation of 7-dione}
Figure PCTKR2022002310-appb-img-000280
Figure PCTKR2022002310-appb-img-000280
수득률: 21 %; 1H-NMR (400MHz, CDCl3) δ 1.72 (2H, m), 1.99 (2H, m), 2.08 (2H, m), 2.29 (2H, m), 2.60 (3H, s), 3.66 (3H, s), 5.76 (1H, q), 7.16 (1H, s), 7.84 (1H, s), 8.35 (1H, s), 8.89 (1H, s)Yield: 21%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.72 (2H, m), 1.99 (2H, m), 2.08 (2H, m), 2.29 (2H, m), 2.60 (3H, s), 3.66 (3H, s), 5.76 (1H, q), 7.16 (1H, s), 7.84 (1H, s), 8.35 (1H, s), 8.89 (1H, s)
실시예 151: 8-사이클로펜틸-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온 {8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione}의 제조Example 151: 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7- Preparation of dione {8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000281
Figure PCTKR2022002310-appb-img-000281
수득률: 9 %; 1H-NMR (400MHz, CDCl3) δ 1.64 (2H, m), 1.91 (4H, m), 2.22 (2H, m), 2.47 (3H, s), 2.83 (3H, s), 3.62 (3H, s), 5.65 (1H, q), 6.90 (1H, s), 7.81 (1H, s), 8.26 (1H, s), 8.43 (1H, s)Yield: 9%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.64 (2H, m), 1.91 (4H, m), 2.22 (2H, m), 2.47 (3H, s), 2.83 (3H, s), 3.62 (3H, s), 5.65 (1H, q), 6.90 (1H, s), 7.81 (1H, s), 8.26 (1H, s), 8.43 (1H, s)
실시예 152: 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(2-옥사스피로[3.5]노난-7-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(2-oxaspiro[3.5]nonan-7-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 152: 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(2-oxaspiro[3.5]nonane-7 -yl)-5,8-dihydropteridine-6,7-dione {5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 8-(2-oxaspiro[3.5]nonan-7-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000282
Figure PCTKR2022002310-appb-img-000282
수득률: 8 %; 1H-NMR (400MHz, CDCl3) δ 1.73 (4H, m), 2.36 (4H, m), 2.62 (3H, s), 3.65 (3H, s), 4.44 (2H, s), 4.58 (2H, s), 5.29 (1H, m), 7.19 (1H, s), 7.84 (1H, s), 8.35 (1H, s), 8.86 (1H, s)Yield: 8 %; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73 (4H, m), 2.36 (4H, m), 2.62 (3H, s), 3.65 (3H, s), 4.44 (2H, s), 4.58 (2H, s), 5.29 (1H, m), 7.19 (1H, s), 7.84 (1H, s), 8.35 (1H, s), 8.86 (1H, s)
실시예 153: 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(2-옥사스피로[3.5]노난-7-일)-5,8-디하이드로프테리딘-6,7-디온 {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(2-oxaspiro[3.5]nonan-7-yl)-5,8-dihydropteridine-6,7-dione}의 제조Example 153: 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(2-oxaspiro[3.5]nonan-7-yl) -5,8-dihydropteridine-6,7-dione {5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(2- Preparation of oxaspiro[3.5]nonan-7-yl)-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000283
Figure PCTKR2022002310-appb-img-000283
수득률: 16 %; 1H-NMR (400MHz, CDCl3) δ 1.57 (4H, m), 2.25 (3H, s), 2.30 (2H, d), 2.51 (2H, q), 3.61 (3H, s), 4.39 (2H, s), 4.50 (2H, s), 5.12 (1H, m), 5.97 (2H, s), 6.60 (1H, s), 6.75 (1H, s), 7.23 (1H, s), 8.22 (1H, s)Yield: 16%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.57 (4H, m), 2.25 (3H, s), 2.30 (2H, d), 2.51 (2H, q), 3.61 (3H, s), 4.39 (2H, s), 4.50 (2H, s), 5.12 (1H, m), 5.97 (2H, s), 6.60 (1H, s), 6.75 (1H, s), 7.23 (1H, s), 8.22 (1H, s)
실시예 154: 8-사이클로부틸-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온 {8-cyclobutyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione}의 제조Example 154: 8-cyclobutyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7- Preparation of dione {8-cyclobutyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000284
Figure PCTKR2022002310-appb-img-000284
수득률: 23 %; 1H-NMR (400MHz, CDCl3) δ 1.77 (2H, m), 2.30 (2H, q), 2.47 (3H, s), 2.83 (3H, s), 2.96 (2H, q), 3.61 (3H, s), 5.54 (1H, q), 6.89 (1H, s), 7.81 (1H, s), 8.25 (1H, s), 8.41 (1H, s)Yield: 23%; 1 H-NMR (400 MHz, CDCl 3 ) δ 1.77 (2H, m), 2.30 (2H, q), 2.47 (3H, s), 2.83 (3H, s), 2.96 (2H, q), 3.61 (3H, s), 5.54 (1H, q), 6.89 (1H, s), 7.81 (1H, s), 8.25 (1H, s), 8.41 (1H, s)
실시예 155: 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 155: 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-5,8- Dihydropteridine-6,7-dione {8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino Preparation of )-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000285
Figure PCTKR2022002310-appb-img-000285
단계 1: 4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-아민 {4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-amine}의 제조Step 1: 4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-amine {4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin- Preparation of 3-amine}
Figure PCTKR2022002310-appb-img-000286
Figure PCTKR2022002310-appb-img-000286
실시예 34의 반응식과 실질적으로 동일한 방법으로 적절한 유도체를 사용하여 표제 화합물을 제조하였다(수득률: 80 %). 1H-NMR (400MHz, CDCl3) δ 2.20 (3H, s), 3.60 (2H, br), 3.92 (3H, s), 7.17 (1H, s), 7.79 (1H, s), 7.83 (1H, s), 7.98 (1H, s)Example 34 and realistically same in a way appropriate derivatives using The title compound was prepared (yield: 80%). 1 H-NMR (400 MHz, CDCl 3 ) δ 2.20 (3H, s), 3.60 (2H, br), 3.92 (3H, s), 7.17 (1H, s), 7.79 (1H, s), 7.83 (1H, s), 7.98 (1H, s)
단계 2: 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Step 2: 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-5,8-di hydropteridine-6,7-dione {8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino) Preparation of -5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000287
Figure PCTKR2022002310-appb-img-000287
제조예 15에서 제조한 2-클로로-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온 29.7 mg, 단계 1에서 제조한 4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-아민 22.8 mg, 세슘카보네이트 65.2 mg, 팔라듐아세테이트 4.5 mg 및 엑스포스 9.5 mg을 다이옥산 2 mL에 투입한 후, 130 ℃에서 30 분 동안 마이크로웨이브를 조사하였다. 반응물을 셀라이트로 여과하고 농축한 후, 잔사물을 Prep-HPLC로 정제하여 목적 화합물을 수득하였다(수득률: 10 %). 1H-NMR (400MHz, CDCl3) δ 1.59 (2H, m), 1.87 (4H, br), 2.18 (2H, m), 2.35 (3H, s), 3.61 (3H, s), 3.97 (3H, s), 5.61 (1H, q), 6.63 (1H, s), 7.37 (1H, s), 7.92 (2H, d), 8.22 (1H, s), 8.80 (1H, s)29.7 mg of 2-chloro-5-methyl-8- (tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione prepared in Preparation Example 15, in step 1 The prepared 4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-amine 22.8 mg, cesium carbonate 65.2 mg, palladium acetate 4.5 mg, and expox 9.5 mg were added to 2 mL dioxane. Then, it was irradiated with microwaves at 130 °C for 30 minutes. The reaction product was filtered through celite and concentrated, and the residue was purified by Prep-HPLC to obtain the target compound (yield: 10%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.59 (2H, m), 1.87 (4H, br), 2.18 (2H, m), 2.35 (3H, s), 3.61 (3H, s), 3.97 (3H, s), 5.61 (1H, q), 6.63 (1H, s), 7.37 (1H, s), 7.92 (2H, d), 8.22 (1H, s), 8.80 (1H, s)
실시예 156: 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온 {8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-5,8-dihydropteridine-6,7-dione}의 제조Example 156: 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-5,8- Dihydropteridine-6,7-dione {8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino Preparation of )-5,8-dihydropteridine-6,7-dione}
Figure PCTKR2022002310-appb-img-000288
Figure PCTKR2022002310-appb-img-000288
실시예 155와 실질적으로 동일한 방법으로 적절한 아민 유도체를 사용하여 표제 화합물을 제조하였다(수득률: 15 %). 1H-NMR (400MHz, CDCl3) δ 1.62 (2H, m), 1.89 (4H, br), 2.20 (2H, m), 2.37 (3H, s), 3.63 (3H, s), 3.99 (3H, s), 5.63 (1H, q), 6.65 (1H, s), 7.39 (1H, s), 7.94 (2H, d), 8.24 (1H, s), 8.83 (1H, s)Example 155 and practically The title compound was prepared in the same manner using the appropriate amine derivative (yield: 15%). 1 H-NMR (400 MHz, CDCl 3 ) δ 1.62 (2H, m), 1.89 (4H, br), 2.20 (2H, m), 2.37 (3H, s), 3.63 (3H, s), 3.99 (3H, s), 5.63 (1H, q), 6.65 (1H, s), 7.39 (1H, s), 7.94 (2H, d), 8.24 (1H, s), 8.83 (1H, s)
실험예 1: DNA-PK 억제 활성 평가Experimental Example 1: DNA-PK inhibitory activity evaluation
DNA-PK에 대한 화합물의 억제 활성은 포스포릴화된 생성물로 전환시키는 형광 표지된 펩티드 기질을 측정하는 TR-FRET에 의해 결정되었다. 초기에 전장 인간 DNAPK 단백질은 50 nM GST-cMyc-p53과 Mg/ATP를 포함하는 버퍼용액에서 인큐베이션되었다. 반응은 Mg/ATP의 혼합물의 추가로 개시되었고, 상온에서 30분 동안 인큐베이션 된 후, 반응은 EDTA를 포함하는 정지용액의 추가로 정지되었다. 마지막으로, 검출 버퍼가 추가되었다(검출 버퍼는 인산화된 p53에 대한, d2-부착된 항-GST 단일 항체와 Europium-부착된 항 인산화 Ser15 항체임). 플레이트는 TRF 모드에서 판독되었다. 그리고, HTRF 신호는 10000 X (Em 665 nm/Em 620 nm) 공식을 적용하였다. 예시 화합물의 DNA-PK 억제 활성은 하기 [표 1]에 제시되어 있다. 본 개시 내용의 화합물이 강력한 DNA-PK 억제 활성을 입증했음을 알 수 있으며, 모든 DNA-PK 효소 효능 검정은 영국 유로핀스에서 수행되었다.The inhibitory activity of compounds against DNA-PK was determined by TR-FRET, which measures the fluorescently labeled peptide substrates that are converted to phosphorylated products. Initially, full-length human DNAPK protein was incubated in a buffer solution containing 50 nM GST-cMyc-p53 and Mg/ATP. The reaction was initiated by addition of a mixture of Mg/ATP, and after incubation at room temperature for 30 minutes, the reaction was stopped by addition of a stop solution containing EDTA. Finally, a detection buffer was added (detection buffer was a d2-attached anti-GST single antibody and Europium-attached anti-phosphorylated Ser15 antibody against phosphorylated p53). Plates were read in TRF mode. And, for the HTRF signal, 10000 X (Em 665 nm/Em 620 nm) formula was applied. The DNA-PK inhibitory activity of exemplary compounds is shown in Table 1 below. It can be seen that the compounds of the present disclosure demonstrated potent DNA-PK inhibitory activity, and all DNA-PK enzyme potency assays were performed in Europins, UK.
실시예Example 저해%Inhibition % 실시예Example 저해%Inhibition % 실시예Example 저해%Inhibition % 실시예Example 저해%Inhibition %
1One 9898 4141 9999 8181 101101 121121 9696
22 8080 4242 9797 8282 100100 122122 9191
33 8383 4343 102102 8383 9595 123123 9191
44 9898 4444 101101 8484 8686 124124 100100
55 9090 4545 102102 8585 9898 125125 8787
66 9898 4646 9595 8686 102102 126126 8787
77 9999 4747 8080 8787 8888 127127 9898
88 8989 4848 8888 8888 8282 128128 9595
99 101101 4949 100100 8989 8686 129129 9595
1010 103103 5050 9393 9090 8484 130130 9595
1111 8686 5151 9393 9191 101101 131131 9393
1212 9595 5252 8080 9292 9090 132132 104104
1313 9292 5353 8888 9393 106106 133133 101101
1414 105105 5454 8181 9494 100100 134134 9191
1515 8484 5555 8787 9595 9696 135135 104104
1616 9292 5656 9090 9696 8686 136136 8181
1717 9494 5757 9393 9797 8484 137137 9999
1818 9393 5858 9595 9898 8484 138138 8282
1919 8383 5959 103103 9999 9090 139139 9898
2020 8282 6060 9696 100100 100100 140140 100100
2121 9898 6161 9292 101101 9191 141141 9999
2222 9999 6262 8686 102102 104104 142142 100100
2323 8181 6363 8686 103103 100100 143143 9999
2424 8080 6464 9696 104104 8585 144144 9797
2525 102102 6565 8888 105105 102102 145145 101101
2626 101101 6666 100100 106106 9292 146146 100100
2727 102102 6767 8888 107107 9999 147147 9999
2828 101101 6868 9191 108108 9696 148148 101101
2929 8888 6969 9494 109109 8888 149149 9595
3030 8787 7070 9999 110110 8989 150150 102102
3131 8383 7171 102102 111111 8989 151151 103103
3232 9292 7272 102102 112112 8787 152152 100100
3333 8686 7373 102102 113113 8686 153153 9595
3434 102102 7474 9898 114114 8989 154154 9595
3535 100100 7575 101101 115115 8484 155155 9292
3636 9393 7676 101101 116116 8282 156156 9595
3737 106106 7777 8989 117117 8484
3838 9494 7878 8080 118118 9898
3939 101101 7979 9090 119119 100100
4040 8383 8080 101101 120120 9797

Claims (13)

  1. 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022002310-appb-img-000289
    Figure PCTKR2022002310-appb-img-000289
    상기 화학식 1에서,In Formula 1,
    Figure PCTKR2022002310-appb-img-000290
    는 단일결합 또는 이중결합이고;
    Figure PCTKR2022002310-appb-img-000290
    is a single bond or a double bond;
    n은 0, 1 또는 2이고;n is 0, 1 or 2;
    X1은 NR1 또는 CR2R3 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000291
    가 이중결합인 경우 R1 또는 R3는 아무 것도 아님(null)};    X 1 is NR 1 or CR 2 R 3 {wherein
    Figure PCTKR2022002310-appb-img-000291
    is a double bond, then R 1 or R 3 is nothing (null)};
    X2는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000292
    가 단일결합인 경우 X2는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고,
    Figure PCTKR2022002310-appb-img-000293
    가 이중결합인 경우 X2는 -CR2- 이며, n이 0인 경우 X2는 아무 것도 아니고(null) X1 및 X3는 직접 연결됨};    X 2 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein,
    Figure PCTKR2022002310-appb-img-000292
    When is a single bond, X 2 is -CR 2 R 3 -, -(C=O)- or -(C=S)-,
    Figure PCTKR2022002310-appb-img-000293
    is a double bond, X 2 is —CR 2 —, and when n is 0, X 2 is null and X 1 and X 3 are directly linked};
    X3는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서, n이 0이고
    Figure PCTKR2022002310-appb-img-000294
    가 단일결합인 경우, X3는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고, n이 0이고
    Figure PCTKR2022002310-appb-img-000295
    가 이중결합인 경우 X3는 -CR2- 임};    X 3 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein n is 0 and
    Figure PCTKR2022002310-appb-img-000294
    When is a single bond, X 3 is -CR 2 R 3 -, -(C=O)- or -(C=S)-, n is 0 and
    Figure PCTKR2022002310-appb-img-000295
    is a double bond, then X 3 is -CR 2 -;
    L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
    Y는 -O-C1-4알킬,
    Figure PCTKR2022002310-appb-img-000296
    ,
    Figure PCTKR2022002310-appb-img-000297
    , 아릴, 또는 헤테로아릴이고 {여기서, 상기
    Figure PCTKR2022002310-appb-img-000298
    ,
    Figure PCTKR2022002310-appb-img-000299
    , 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};    Y is -OC 1-4 alkyl,
    Figure PCTKR2022002310-appb-img-000296
    ,
    Figure PCTKR2022002310-appb-img-000297
    , aryl, or heteroaryl {wherein
    Figure PCTKR2022002310-appb-img-000298
    ,
    Figure PCTKR2022002310-appb-img-000299
    , aryl, or one or more H of heteroaryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo };
    W1은 -CH2-, -NH-, -O-, 또는 -S-이고;W 1 is -CH 2 -, -NH-, -O-, or -S-;
    W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
    a 내지 d는 각각 독립적으로 0, 1, 2, 또는 3이고;a to d are each independently 0, 1, 2, or 3;
    L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
    Z는 -Z1-L3-Z2이고;Z is -Z 1 -L 3 -Z 2 ;
    Z1은 아릴, 헤테로아릴, 또는 Z 1 is aryl, heteroaryl, or
    Figure PCTKR2022002310-appb-img-000300
    이고 {여기서, 고리 A는 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
    Figure PCTKR2022002310-appb-img-000301
    의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있으며; 상기 헤테로아릴이
    Figure PCTKR2022002310-appb-img-000302
    인 경우 n은 0이 아님};
    Figure PCTKR2022002310-appb-img-000300
    and {wherein ring A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; At least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NH 2 , - NR 4 R 5 , —OH, —OR 6 , or —halo; remind
    Figure PCTKR2022002310-appb-img-000301
    one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-; The heteroaryl
    Figure PCTKR2022002310-appb-img-000302
    n is non-zero if };
    L3는 -(C1-4알킬)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -(C=O)O-(C1-4알킬)-, -NH-, -O-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C 1-4 alkyl)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C =O)O-, -(C=O)O-(C 1-4 alkyl)-, -NH-, -O-, -OS(=O) 2 -, -S-, -S(=O) -, -S(=O) 2 -, or nothing (null);
    Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -OH, -O-C1-4알킬, 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein said cycloalkyl, cycloalkenyl, heterocyclo one or more H of alkyl, or heterocycloalkenyl, may be substituted with -C 1-4 alkyl or -(C=O)-; at least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -OH, -OC 1- 4 may be substituted with alkyl, or -halo};
    R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
    R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
    R4 내지 R6는 각각 독립적으로 -C1-4알킬이다.R 4 to R 6 are each independently —C 1-4 alkyl.
  2. 제 1 항에 있어서,The method of claim 1,
    Figure PCTKR2022002310-appb-img-000303
    는 단일결합 또는 이중결합이고;
    Figure PCTKR2022002310-appb-img-000303
    is a single bond or a double bond;
    n은 0 또는 1이고;n is 0 or 1;
    X1은 NR1 또는 CR2R3 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000304
    가 이중결합인 경우 R1 또는 R3는 아무 것도 아님(null)};    X 1 is NR 1 or CR 2 R 3 {wherein
    Figure PCTKR2022002310-appb-img-000304
    is a double bond, then R 1 or R 3 is nothing (null)};
    X2는 -CR2R3-, -CR2-, 또는 -(C=O)- 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000305
    가 단일결합인 경우 X2는 -CR2R3- 또는 -(C=O)- 이고,
    Figure PCTKR2022002310-appb-img-000306
    가 이중결합인 경우 X2는 -CR2- 이며, n이 0인 경우 X2는 아무 것도 아니고(null) X1 및 X3는 직접 연결됨};    X 2 is -CR 2 R 3 -, -CR 2 -, or -(C=O)- and {wherein,
    Figure PCTKR2022002310-appb-img-000305
    When is a single bond, X 2 is -CR 2 R 3 - or -(C=O)-,
    Figure PCTKR2022002310-appb-img-000306
    is a double bond, X 2 is —CR 2 —, and when n is 0, X 2 is null and X 1 and X 3 are directly linked};
    X3는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서, n이 0이고
    Figure PCTKR2022002310-appb-img-000307
    가 단일결합인 경우, X3는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고, n이 0이고
    Figure PCTKR2022002310-appb-img-000308
    가 이중결합인 경우 X3는 -CR2- 임};    X 3 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein n is 0 and
    Figure PCTKR2022002310-appb-img-000307
    When is a single bond, X 3 is -CR 2 R 3 -, -(C=O)- or -(C=S)-, n is 0 and
    Figure PCTKR2022002310-appb-img-000308
    is a double bond, then X 3 is -CR 2 -;
    L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
    Y는 -O-C1-4알킬,
    Figure PCTKR2022002310-appb-img-000309
    ,
    Figure PCTKR2022002310-appb-img-000310
    , 또는 아릴이고 {여기서, 상기
    Figure PCTKR2022002310-appb-img-000311
    ,
    Figure PCTKR2022002310-appb-img-000312
    , 또는 아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};    Y is -OC 1-4 alkyl,
    Figure PCTKR2022002310-appb-img-000309
    ,
    Figure PCTKR2022002310-appb-img-000310
    , or aryl, {wherein
    Figure PCTKR2022002310-appb-img-000311
    ,
    Figure PCTKR2022002310-appb-img-000312
    , or one or more H of aryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo};
    W1은 -CH2-, -O-, 또는 -S-이고;W 1 is —CH 2 —, —O—, or —S—;
    W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
    a 내지 d는 각각 독립적으로 0, 1, 또는 2이고;a to d are each independently 0, 1, or 2;
    L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
    Z는 -Z1-L3-Z2이고, Z is -Z 1 -L 3 -Z 2 ,
    Z1은 아릴, 헤테로아릴, 또는
    Figure PCTKR2022002310-appb-img-000313
    이고 {여기서, 고리 A는 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
    Figure PCTKR2022002310-appb-img-000314
    의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있으며; 상기 헤테로아릴이
    Figure PCTKR2022002310-appb-img-000315
    인 경우 n은 0이 아님};    Z 1 is aryl, heteroaryl, or
    Figure PCTKR2022002310-appb-img-000313
    and {wherein ring A is heterocycloalkyl or heterocycloalkenyl; at least one H of said aryl or heteroaryl is substituted with -C 1-4 alkyl, -C 1-4 haloalkyl, -CN, -NH 2 , -NR 4 R 5 , -OH, -OR 6 , or -halo can be; remind
    Figure PCTKR2022002310-appb-img-000314
    one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-; The heteroaryl
    Figure PCTKR2022002310-appb-img-000315
    n is non-zero if };
    L3는 -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -NH-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C=O)O-, -NH-, -OS(=O) 2 - , -S-, -S(=O)-, -S(=O) 2 -, or nothing;
    Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein at least one H of the heterocycloalkyl, or heterocycloalkenyl is -C may be substituted with 1-4 alkyl or -(C=O)-; one or more H of said aryl or heteroaryl may be substituted with -C 1-4 alkyl or -halo};
    R은 -H이고; R is -H;
    R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
    R4 내지 R6는 각각 독립적으로 -C1-4알킬인;R 4 to R 6 are each independently —C 1-4 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제 1 항에 있어서,The method of claim 1,
    [화학식 2][Formula 2]
    Figure PCTKR2022002310-appb-img-000316
    Figure PCTKR2022002310-appb-img-000316
    상기 화학식 2에서,In Formula 2,
    X1은 NR1 또는 CR2R3 이고;X 1 is NR 1 or CR 2 R 3 ;
    X3는 -(C=O)- 또는 -(C=S)- 이고;X 3 is -(C=O)- or -(C=S)-;
    L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
    Y는 -O-C1-4알킬,
    Figure PCTKR2022002310-appb-img-000317
    ,
    Figure PCTKR2022002310-appb-img-000318
    , 아릴, 또는 헤테로아릴이고 {여기서, 상기
    Figure PCTKR2022002310-appb-img-000319
    ,
    Figure PCTKR2022002310-appb-img-000320
    , 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};    Y is -OC 1-4 alkyl,
    Figure PCTKR2022002310-appb-img-000317
    ,
    Figure PCTKR2022002310-appb-img-000318
    , aryl, or heteroaryl {wherein
    Figure PCTKR2022002310-appb-img-000319
    ,
    Figure PCTKR2022002310-appb-img-000320
    , aryl, or one or more H of heteroaryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo };
    W1은 -CH2-, -NH-, -O-, 또는 -S-이고;W 1 is -CH 2 -, -NH-, -O-, or -S-;
    W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
    a 내지 d는 각각 독립적으로 0, 1, 2, 또는 3이고;a to d are each independently 0, 1, 2, or 3;
    L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
    Z는 -Z1-L3-Z2이고;Z is -Z 1 -L 3 -Z 2 ;
    Z1은 아릴, 헤테로아릴, 또는
    Figure PCTKR2022002310-appb-img-000321
    이고 {여기서, 고리 A는 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
    Figure PCTKR2022002310-appb-img-000322
    의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};    Z 1 is aryl, heteroaryl, or
    Figure PCTKR2022002310-appb-img-000321
    and {wherein ring A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; At least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NH 2 , - NR 4 R 5 , —OH, —OR 6 , or —halo; remind
    Figure PCTKR2022002310-appb-img-000322
    one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
    L3는 -(C1-4알킬)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -(C=O)O-(C1-4알킬)-, -NH-, -O-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C 1-4 alkyl)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C =O)O-, -(C=O)O-(C 1-4 alkyl)-, -NH-, -O-, -OS(=O) 2 -, -S-, -S(=O) -, -S(=O) 2 -, or nothing (null);
    Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -OH, -O-C1-4알킬, 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein said cycloalkyl, cycloalkenyl, heterocyclo one or more H of alkyl, or heterocycloalkenyl, may be substituted with -C 1-4 alkyl or -(C=O)-; at least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -OH, -OC 1- 4 may be substituted with alkyl, or -halo};
    R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
    R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
    R4 내지 R6는 각각 독립적으로 -C1-4알킬인;R 4 to R 6 are each independently —C 1-4 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제 3 항에 있어서,4. The method of claim 3,
    [화학식 2-1][Formula 2-1]
    Figure PCTKR2022002310-appb-img-000323
    Figure PCTKR2022002310-appb-img-000323
    상기 화학식 2-1에서,In Formula 2-1,
    X3는 -(C=O)- 또는 -(C=S)- 이고;X 3 is -(C=O)- or -(C=S)-;
    L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
    Y는 -O-C1-4알킬,
    Figure PCTKR2022002310-appb-img-000324
    ,
    Figure PCTKR2022002310-appb-img-000325
    , 또는 아릴이고 {여기서, 상기
    Figure PCTKR2022002310-appb-img-000326
    ,
    Figure PCTKR2022002310-appb-img-000327
    , 또는 아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};    Y is -OC 1-4 alkyl,
    Figure PCTKR2022002310-appb-img-000324
    ,
    Figure PCTKR2022002310-appb-img-000325
    , or aryl, {wherein
    Figure PCTKR2022002310-appb-img-000326
    ,
    Figure PCTKR2022002310-appb-img-000327
    , or one or more H of aryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo};
    W1은 -CH2-, -O-, 또는 -S-이고;W 1 is —CH 2 —, —O—, or —S—;
    W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
    a 내지 d는 각각 독립적으로 0, 1, 또는 2이고;a to d are each independently 0, 1, or 2;
    L2는 아무 것도 아니고(null);L 2 is null;
    Z는 -Z1-L3-Z2이고, Z is -Z 1 -L 3 -Z 2 ,
    Z1은 아릴, 헤테로아릴, 또는 Z 1 is aryl, heteroaryl, or
    Figure PCTKR2022002310-appb-img-000328
    이고 {여기서, 고리 A는 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
    Figure PCTKR2022002310-appb-img-000329
    의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};
    Figure PCTKR2022002310-appb-img-000328
    and {wherein ring A is heterocycloalkyl or heterocycloalkenyl; at least one H of said aryl or heteroaryl is substituted with -C 1-4 alkyl, -C 1-4 haloalkyl, -CN, -NH 2 , -NR 4 R 5 , -OH, -OR 6 , or -halo can be; remind
    Figure PCTKR2022002310-appb-img-000329
    one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
    L3는 -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -NH-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C=O)O-, -NH-, -OS(=O) 2 - , -S-, -S(=O)-, -S(=O) 2 -, or nothing;
    Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein at least one H of the heterocycloalkyl, or heterocycloalkenyl is -C may be substituted with 1-4 alkyl or -(C=O)-; one or more H of said aryl or heteroaryl may be substituted with -C 1-4 alkyl or -halo};
    R은 -H이고; R is -H;
    R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
    R4 내지 R6는 각각 독립적으로 -C1-4알킬인;R 4 to R 6 are each independently —C 1-4 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 제 1 항에 있어서,The method of claim 1,
    [화학식 3][Formula 3]
    Figure PCTKR2022002310-appb-img-000330
    Figure PCTKR2022002310-appb-img-000330
    상기 화학식 3에서,In Formula 3,
    Figure PCTKR2022002310-appb-img-000331
    는 단일결합 또는 이중결합이고;
    Figure PCTKR2022002310-appb-img-000331
    is a single bond or a double bond;
    X1은 NR1 또는 CR2R3 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000332
    가 이중결합인 경우 R1 또는 R3는 아무 것도 아님(null)};    X 1 is NR 1 or CR 2 R 3 {wherein
    Figure PCTKR2022002310-appb-img-000332
    is a double bond, then R 1 or R 3 is nothing (null)};
    X2는 -CR2R3-, -CR2-, -(C=O)- 또는 -(C=S)- 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000333
    가 단일결합인 경우 X2는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고,
    Figure PCTKR2022002310-appb-img-000334
    가 이중결합인 경우 X2는 -CR2-임};    X 2 is -CR 2 R 3 -, -CR 2 -, -(C=O)- or -(C=S)-, {wherein,
    Figure PCTKR2022002310-appb-img-000333
    When is a single bond, X 2 is -CR 2 R 3 -, -(C=O)- or -(C=S)-,
    Figure PCTKR2022002310-appb-img-000334
    is a double bond, X 2 is -CR 2 -;
    X3는 -CR2R3-, -CR2-, -(C=O)-, 또는 -(C=S)- 이고 {여기서, n이 0이고
    Figure PCTKR2022002310-appb-img-000335
    가 단일결합인 경우, X3는 -CR2R3-, -(C=O)- 또는 -(C=S)- 이고, n이 0이고
    Figure PCTKR2022002310-appb-img-000336
    가 이중결합인 경우 X3는 -CR2- 임};    X 3 is -CR 2 R 3 -, -CR 2 -, -(C=O)-, or -(C=S)-, {wherein n is 0 and
    Figure PCTKR2022002310-appb-img-000335
    When is a single bond, X 3 is -CR 2 R 3 -, -(C=O)- or -(C=S)-, n is 0 and
    Figure PCTKR2022002310-appb-img-000336
    is a double bond, then X 3 is -CR 2 -;
    L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
    Y는 -O-C1-4알킬,
    Figure PCTKR2022002310-appb-img-000337
    ,
    Figure PCTKR2022002310-appb-img-000338
    , 아릴, 또는 헤테로아릴이고 {여기서, 상기
    Figure PCTKR2022002310-appb-img-000339
    ,
    Figure PCTKR2022002310-appb-img-000340
    , 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};    Y is -OC 1-4 alkyl,
    Figure PCTKR2022002310-appb-img-000337
    ,
    Figure PCTKR2022002310-appb-img-000338
    , aryl, or heteroaryl {wherein
    Figure PCTKR2022002310-appb-img-000339
    ,
    Figure PCTKR2022002310-appb-img-000340
    , aryl, or one or more H of heteroaryl may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo };
    W1은 -CH2-, -NH-, -O-, 또는 -S-이고;W 1 is -CH 2 -, -NH-, -O-, or -S-;
    W2는 -CH- 또는 -N-이고;W 2 is -CH- or -N-;
    a 내지 d는 각각 독립적으로 0, 1, 2, 또는 3이고;a to d are each independently 0, 1, 2, or 3;
    L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
    Z는 -Z1-L3-Z2이고; Z is -Z 1 -L 3 -Z 2 ;
    Z1은 아릴, 헤테로아릴, 또는
    Figure PCTKR2022002310-appb-img-000341
    이고 {여기서, 고리 A는 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NH2, -NR4R5, -OH, -OR6, 또는 -할로로 치환될 수 있고; 상기
    Figure PCTKR2022002310-appb-img-000342
    의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};    Z 1 is aryl, heteroaryl, or
    Figure PCTKR2022002310-appb-img-000341
    and {wherein ring A is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; At least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NH 2 , - NR 4 R 5 , —OH, —OR 6 , or —halo; remind
    Figure PCTKR2022002310-appb-img-000342
    one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
    L3는 -(C1-4알킬)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C1-4알킬)-, -(C=O)O-, -(C=O)O-(C1-4알킬)-, -NH-, -O-, -O-S(=O)2-, -S-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null);L 3 is -(C 1-4 alkyl)-, -(C=O)-, -(C=O)NH-, -(C=O)NH-(C 1-4 alkyl)-, -(C =O)O-, -(C=O)O-(C 1-4 alkyl)-, -NH-, -O-, -OS(=O) 2 -, -S-, -S(=O) -, -S(=O) 2 -, or nothing (null);
    Z2는 -H, -C1-4알킬, -C1-4하이드록시알킬, -C1-4알킬-(O-C1-4알킬), -C1-4알킬-(O-C1-4알킬)(O-C1-4알킬), 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 헤테로사이클로알케닐, 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 사이클로알킬, 사이클로알케닐, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있고; 상기 아릴, 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -OH, -O-C1-4알킬, 또는 -할로로 치환될 수 있음};Z 2 is -H, -C 1-4 alkyl, -C 1-4 hydroxyalkyl, -C 1-4 alkyl-(OC 1-4 alkyl), -C 1-4 alkyl-(OC 1-4 alkyl) ) (OC 1-4 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, or null {wherein said cycloalkyl, cycloalkenyl, heterocyclo one or more H of alkyl, or heterocycloalkenyl, may be substituted with -C 1-4 alkyl or -(C=O)-; at least one H of said aryl or heteroaryl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -OH, -OC 1- 4 may be substituted with alkyl, or -halo};
    R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
    R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
    R4 내지 R6는 각각 독립적으로 -C1-4알킬인;R 4 to R 6 are each independently —C 1-4 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  6. 제 1 항에 있어서,The method of claim 1,
    [화학식 3-1][Formula 3-1]
    Figure PCTKR2022002310-appb-img-000343
    Figure PCTKR2022002310-appb-img-000343
    상기 화학식 3-1에서,In Formula 3-1,
    Figure PCTKR2022002310-appb-img-000344
    는 단일결합 또는 이중결합이고 {여기서,
    Figure PCTKR2022002310-appb-img-000345
    가 이중결합인 경우 R3는 아무 것도 아님(null)};
    Figure PCTKR2022002310-appb-img-000344
    is a single bond or a double bond {where,
    Figure PCTKR2022002310-appb-img-000345
    R 3 is nothing when is a double bond (null)};
    X2는 -CR2R3-, -CR2- 또는 -(C=O)- 이고 {여기서,
    Figure PCTKR2022002310-appb-img-000346
    가 단일결합인 경우 X2는 -CR2R3- 또는 -(C=O)- 이고,
    Figure PCTKR2022002310-appb-img-000347
    가 이중결합인 경우 X2는 -CR2- 임};    X 2 is -CR 2 R 3 -, -CR 2 - or -(C=O)- and {wherein,
    Figure PCTKR2022002310-appb-img-000346
    When is a single bond, X 2 is -CR 2 R 3 - or -(C=O)-,
    Figure PCTKR2022002310-appb-img-000347
    X 2 is -CR 2 - when is a double bond;
    L1은 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 1 is -(C 1-4 alkyl)- or nothing (null);
    Y는
    Figure PCTKR2022002310-appb-img-000348
    또는
    Figure PCTKR2022002310-appb-img-000349
    이고 {여기서, 상기
    Figure PCTKR2022002310-appb-img-000350
    또는
    Figure PCTKR2022002310-appb-img-000351
    의 하나 이상의 H는 -C1-4알킬, -OH, -O-C1-4알킬, -O(C=O)-C1-4알킬, 또는 -할로로 치환될 수 있음};    Y is
    Figure PCTKR2022002310-appb-img-000348
    or
    Figure PCTKR2022002310-appb-img-000349
    and {wherein the
    Figure PCTKR2022002310-appb-img-000350
    or
    Figure PCTKR2022002310-appb-img-000351
    one or more H of may be substituted with -C 1-4 alkyl, -OH, -OC 1-4 alkyl, -O(C=O)-C 1-4 alkyl, or -halo};
    W1은 -CH2- 또는 -O-이고;W 1 is —CH 2 — or —O—;
    W2는 -CH-이고;W 2 is —CH—;
    a 내지 d는 각각 독립적으로 1 또는 2이고;a to d are each independently 1 or 2;
    L2는 -(C1-4알킬)- 또는 아무 것도 아니고(null);L 2 is -(C 1-4 alkyl)- or nothing (null);
    Z는 -Z1-L3-Z2이고, Z is -Z 1 -L 3 -Z 2 ,
    Z1은 아릴, 헤테로아릴, 또는
    Figure PCTKR2022002310-appb-img-000352
    이고 {여기서, 고리 A는 헤테로사이클로알킬 또는 헤테로사이클로알케닐이고; 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -OH, 또는 -할로로 치환될 수 있고; 상기
    Figure PCTKR2022002310-appb-img-000353
    의 하나 이상의 H는 -C1-4알킬 또는 -(C=O)-로 치환될 수 있음};    Z 1 is aryl, heteroaryl, or
    Figure PCTKR2022002310-appb-img-000352
    and {wherein ring A is heterocycloalkyl or heterocycloalkenyl; one or more H of said aryl or heteroaryl may be substituted with -C 1-4 alkyl, -OH, or -halo; remind
    Figure PCTKR2022002310-appb-img-000353
    one or more H of may be substituted with -C 1-4 alkyl or -(C=O)-};
    L3는 -(C=O)NH- 또는 아무 것도 아니고(null);L 3 is -(C=O)NH- or nothing (null);
    Z2는 -H, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 헤테로아릴의 하나 이상의 H는 -C1-4알킬로 치환될 수 있음};Z 2 is —H, heteroaryl, or null {wherein one or more H of the heteroaryl may be substituted with —C 1-4 alkyl};
    R은 -H 또는 -C1-4알킬이고; R is -H or -C 1-4 alkyl;
    R1 내지 R3는 각각 독립적으로 -H 또는 -C1-4알킬인;R 1 to R 3 are each independently —H or —C 1-4 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  7. 제 1 항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염:The compound represented by Formula 1 is selected from the group consisting of the following compounds, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    (1) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(1) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one;
    (2) 7-메틸-2-((6-메틸퀴놀린-7-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(2) 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8 -On;
    (3) 2-(벤조[d]티아졸-6-일아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(3) 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8 -On;
    (4) 2-((5-히드록시나프탈렌-2-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(4) 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one;
    (5) 7-메틸-2-((5-메틸-1H-인돌-6-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(5) 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one;
    (6) 2-((5-클로로벤조[d]옥사졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(6) 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro- 8H-purin-8-one;
    (7) 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(7) 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one;
    (8) 2,2-디메틸-7-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-2H-벤조[b][1,4]옥사진-3(4H)-온;(8) 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)-2H-benzo[b][1,4]oxazin-3(4H)-one;
    (9) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(9) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
    (10) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(10) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purin-8-one;
    (11) 2-((4,7-디메틸-2-옥소-2H-크로멘-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(11) 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
    (12) 7-메틸-2-((4-메틸-6-(4-메틸-1H-이미다졸-1-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(12) 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
    (13) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리노니트릴;(13) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) picolinonitrile;
    (14) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(14) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )picolinamide;
    (15) 메틸 5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)티오펜-2-카르복실레이트;(15) methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)thiophene -2-carboxylate;
    (16) 메틸 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜리네이트;(16) methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) amino) picolinate;
    (17) N,4-디메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(17) N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)picolinamide;
    (18) 7-메틸-2-((4-메틸-6-(메틸티오)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(18) 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one;
    (19) 7-메틸-2-((4-메틸-6-(트리플루오로메틸)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(19) 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one;
    (20) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온;(20) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purine-8- On;
    (21) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온;(21) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purine -8-one;
    (22) 2-((4,7-디메틸-2-옥소-2H-크로멘-6-일)아미노)-7-메틸-9-페닐-7,9-디하이드로-8H-푸린-8-온;(22) 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purine-8- On;
    (23) 7-메틸-2-((4-메틸-6-(트리플루오로메틸)피리딘-3-일)아미노)-9-페닐-7,9-디하이드로-8H-푸린-8-온;(23) 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one ;
    (24) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(24) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-thiopyran -4-yl)-7,9-dihydro-8H-purin-8-one;
    (25) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(스피로[3.3]헵탄-2-일)-7,9-디하이드로-8H-푸린-8-온;(25) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7,9-dihydro -8H-purin-8-one;
    (26) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(스피로[3.3]헵탄-2-일)-7,9-디하이드로-8H-푸린-8-온;(26) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[3.3]heptan-2-yl)- 7,9-dihydro-8H-purin-8-one;
    (27) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-9-(3-메톡시사이클로부틸)-7-메틸-7,9-디하이드로-8H-푸린-8-온;(27) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H- purin-8-one;
    (28) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-옥사스피로[3.3]헵탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(28) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9 -dihydro-8H-purin-8-one;
    (29) 7-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(29) 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5] nonan-7-yl)-7,9-dihydro-8H-purin-8-one;
    (30) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-티온;(30) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purine-8-thione;
    (31) 4-메틸-5-((7-메틸-9-(테트라하이드로-2H-피란-4-일)-8-티옥소-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(31) 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl) amino)picolinamide;
    (32) 7-메틸-2-((4-메틸-6-((1-메틸-1H-피라졸-4-일)아미노)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(32) 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
    (33) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피리딘-2-일 메탄설포네이트;(33) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) pyridin-2-yl methanesulfonate;
    (34) 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(34) 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
    (35) 7-메틸-2-((4-메틸-6-(3-메틸티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(35) 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
    (36) 7-메틸-2-((4-메틸-6-(5-메틸티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(36) 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
    (37) 7-메틸-2-((4-메틸-6-(티오펜-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(37) 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
    (38) 2-((6-(푸란-3-일)-2-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(38) 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
    (39) 7-메틸-2-((4-메틸-6-(티오펜-3-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(39) 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
    (40) 7-메틸-2-((4-메틸-6-(5-메틸푸란-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(40) 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) -7,9-dihydro-8H-purin-8-one;
    (41) 2-((6-(푸란-2-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(41) 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one;
    (42) 7-메틸-2-((4-메틸-6-(2-메틸옥사졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(42) 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
    (43) 7-메틸-2-((4-메틸-6-(2-메틸티아졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(43) 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
    (44) 7-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(44) 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one;
    (45) 7-메틸-2-((4-메틸-6-(옥사졸-5-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(45) 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
    (46) 7-메틸-2-((4-메틸-6-(옥사졸-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(46) 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
    (47) 2-((6-(벤조[d][1,3]디옥솔-5-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(47) 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
    (48) 7-메틸-2-((4-메틸-6-(5-메틸이소옥사졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(48) 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one;
    (49) 7-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(49) 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
    (50) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피롤-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(50) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one;
    (51) 2-((6-(2,5-디하이드로푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(51) 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one;
    (52) 2-((6-(4,5-디하이드로푸란-3-일)-4-메틸피리딘-3-일)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(52) 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one;
    (53) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(53) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5] nonan-7-yl)-7,9-dihydro-8H-purin-8-one;
    (54) 7-메틸-2-((4-메틸-6-(티오펜-2-일)피리딘-3-일)아미노)-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온;(54) 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7,9-di hydro-8H-purin-8-one;
    (55) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온;(55) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-morpholino-7,9- dihydro-8H-purin-8-one;
    (56) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(56) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(spiro[2.5]octane-6 -yl)-7,9-dihydro-8H-purin-8-one;
    (57) 7-에틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(57) 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
    (58) 7-에틸-2-((4-메틸-6-(옥사졸-2-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(58) 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one;
    (59) 7-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(59) 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one;
    (60) 2-((5-플루오로-2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(60) 2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one;
    (61) 2-((5-플루오로-2-메틸-4-(2-메틸옥사졸-5-일)페닐)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(61) 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one;
    (62) 7-메틸-2-((4-메틸-6-(메틸술포닐)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(62) 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- dihydro-8H-purin-8-one;
    (63) 7-메틸-2-((4-메틸-6-(메틸술피닐)피리딘-3-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(63) 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- dihydro-8H-purin-8-one;
    (64) N-(2-메톡시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(64) N-(2-methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro -7H-purin-2-yl)amino)picolinamide;
    (65) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-N-((테트라하이드로푸란-2-일)메틸)피콜린아미드;(65) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )-N-((tetrahydrofuran-2-yl)methyl)picolinamide;
    (66) N-(2-히드록시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(66) N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro -7H-purin-2-yl)amino)picolinamide;
    (67) N-(2,2-디메톡시에틸)-4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(67) N-(2,2-dimethoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9- dihydro-7H-purin-2-yl)amino)picolinamide;
    (68) 4-메틸-N-(1-메틸-1H-피라졸-4-일)-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)피콜린아미드;(68) 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) -8,9-dihydro-7H-purin-2-yl)amino)picolinamide;
    (69) 4-메틸-5-((7-메틸-8-옥소-9-(테트라하이드로-2H-피란-4-일)-8,9-디하이드로-7H-푸린-2-일)아미노)-N-(옥세탄-3-일)피콜린아미드;(69) 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )-N-(oxetan-3-yl)picolinamide;
    (70) 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(70) 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (71) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(71) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl )-7,9-dihydro-8H-purin-8-one;
    (72) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(72) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9- dihydro-8H-purin-8-one;
    (73) 7-메틸-2-((7-메틸퀴놀린-6-일)아미노)-9-(테트라하이드로-2H-티오피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(73) 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purine- 8-one;
    (74) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(74) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)- 7,9-dihydro-8H-purin-8-one;
    (75) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(75) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9 -dihydro-8H-purin-8-one;
    (76) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(2-옥사스피로[3.5]노난-7-일)-7,9-디하이드로-8H-푸린-8-온;(76) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(2-oxaspiro[3.5]nonane-7- yl)-7,9-dihydro-8H-purin-8-one;
    (77) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온;(77) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H- purin-8-one;
    (78) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(2-모르폴리노에틸)-7,9-디하이드로-8H-푸린-8-온;(78) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9-dihydro -8H-purin-8-one;
    (79) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온;(79) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purine- 8-one;
    (80) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-모르폴리노-7,9-디하이드로-8H-푸린-8-온;(80) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one ;
    (81) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(81) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)- 7,9-dihydro-8H-purin-8-one;
    (82) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-(스피로[2.5]옥탄-6-일)-7,9-디하이드로-8H-푸린-8-온;(82) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9 -dihydro-8H-purin-8-one;
    (83) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-7-메틸-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(83) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7, 9-dihydro-8H-purin-8-one;
    (84) 7-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(84) 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl) -7,9-dihydro-8H-purin-8-one;
    (85) 7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(85) 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl) )methyl)-7,9-dihydro-8H-purin-8-one;
    (86) 7-메틸-2-((7-메틸퀴놀린-6-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(86) 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H- purin-8-one;
    (87) 7-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-9-((테트라하이드로-2H-피란-4-일)메틸)-7,9-디하이드로-8H-푸린-8-온;(87) 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-9-((tetrahydro-2H-pyran) -4-yl)methyl)-7,9-dihydro-8H-purin-8-one;
    (88) 9-(2-메톡시에틸)-7-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-7,9-디하이드로-8H-푸린-8-온;(88) 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-7,9- dihydro-8H-purin-8-one;
    (89) 7-메틸-2-((6-메틸-2-옥소-2,3-디하이드로-1H-벤조[d]이미다졸-5-일)아미노)-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(89) 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-9-(tetrahydro-2H- pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
    (90) 6-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(90) 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (91) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(91) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;
    (92) 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(92) 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3 -d]pyrimidin-7(8H)-one;
    (93) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(93) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) pyrido[2,3-d]pyrimidin-7(8H)-one;
    (94) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(94) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[ 2,3-d]pyrimidin-7(8H)-one;
    (95) 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온; (95) 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one;
    (96) 5-에틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(96) 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (97) 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(97) 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one;
    (98) 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온;(98) 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) )amino)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (99) 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)피리도[2,3-d]피리미딘-7(8H)-온;(99) 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H- pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (100) 8-사이클로헥실-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온;(100) 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3 -d]pyrimidin-7(8H)-one;
    (101) (1R,4R)-4-(5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)-7-옥소피리도[2,3-d]피리미딘-8(7H)-일)사이클로헥실아세테이트;(101) (1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7 -oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate;
    (102) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온; (102) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-di hydropyrido[2,3-d]pyrimidin-7(6H)-one;
    (103) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(103) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
    (104) 2-((6-브로모-4-메틸피리딘-3-일)아미노)-5-에틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온; (104) 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyri do[2,3-d]pyrimidin-7(6H)-one;
    (105) 4-메틸-5-((5-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜린아미드;(105) 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrido midin-2-yl)amino)picolinamide;
    (106) 4-메틸-5-((6-메틸-7-옥소-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로피리도[2,3-d]피리미딘-2-일)아미노)피콜린아미드;(106) 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrido midin-2-yl)amino)picolinamide;
    (107) 8-((1R,4R)-4-히드록시사이클로헥실)-5-메틸-2-((7-메틸-[1,2,4]트리아졸로[1,5-a]피리딘-6-일)아미노)피리도[2,3-d]피리미딘-7(8H)-온;(107) 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (108) 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(108) 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine-7 (8H)-one;
    (109) 2-((2-(6-메톡시피리딘-3-일)에틸)아미노)-7-메틸-9-(테트라하이드로-2H-피란-4-일)-7,9-디하이드로-8H-푸린-8-온;(109) 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro -8H-purin-8-one;
    (110) 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(110) 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d] pyrimidin-7(8H)-one;
    (111) 2-((3,4-디메톡시펜에틸)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(111) 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3 -d]pyrimidin-7(6H)-one;
    (112) 2-((2-(3,4-디메톡시페닐)프로필)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(112) 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido [2,3-d]pyrimidin-7(6H)-one;
    (113) 5-메틸-2-((4-메틸-6-(3-메틸이소티아졸-5-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온; (113) 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one;
    (114) 5-메틸-2-((2-메틸-4-(1-메틸-1H-피라졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)피리도[2,3-d]피리미딘-7(8H)-온;(114) 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl) pyrido[2,3-d]pyrimidin-7(8H)-one;
    (115) 2-((6-(푸란-3-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(115) 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
    (116) 2-((6-(푸란-2-일)-4-메틸피리딘-3-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(116) 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
    (117) 5-에틸-2-((4-메틸-6-(티오펜-3-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로피리도[2,3-d]피리미딘-7(6H)-온;(117) 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;
    (118) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(118) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-di hydropteridine-6,7-dione;
    (119) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(119) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione;
    (120) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(120) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropteridine-6,7-dione;
    (121) 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(121) 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran- 4-yl)-5,8-dihydropteridine-6,7-dione;
    (122) 5-메틸-2-((2-메틸-4-(1-메틸-1H-이미다졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(122) 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione;
    (123) 5-메틸-2-((2-메틸-4-(1-메틸-1H-피라졸-4-일)페닐)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(123) 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl) -5,8-dihydropteridine-6,7-dione;
    (124) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-5,8-디하이드로프테리딘-6,7-디온;(124) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6, 7-dione;
    (125) 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(125) 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-((tetrahydro-2H-pyran) -4-yl)methyl)-5,8-dihydropteridin-6,7-dione;
    (126) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(126) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl) -5,8-dihydropteridine-6,7-dione;
    (127) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(127) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl) )methyl)-5,8-dihydropteridine-6,7-dione;
    (128) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(128) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-5, 8-dihydropteridine-6,7-dione;
    (129) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-5,8-디하이드로프테리딘-6,7-디온;(129) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine -6,7-dione;
    (130) 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(130) 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8 -dihydropteridine-6,7-dione;
    (131) 8-(4,4-디플루오로사이클로헥실)-5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(131) 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) )amino)-5,8-dihydropteridine-6,7-dione;
    (132) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(132) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-di hydropteridin-6(5H)-one;
    (133) 5-메틸-2-((7-메틸-[1,2,4]트라이아졸로[1,5-a]피리딘-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(133) 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one;
    (134) 2-((2,6-디메틸벤조[d]티아졸-5-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(134) 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-di hydropteridin-6(5H)-one;
    (135) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(135) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl) -7,8-dihydropteridin-6(5H)-one;
    (136) 2-((5-히드록시나프탈렌-2-일)아미노)-5-메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(136) 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6 (5H)-one;
    (137) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(137) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7, 8-dihydropteridin-6(5H)-one;
    (138) 5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(138) 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran- 4-yl)-7,8-dihydropteridin-6(5H)-one;
    (139) 5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(139) 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran- 4-yl)-7,8-dihydropteridin-6(5H)-one;
    (140) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(140) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6( 5H)-on;
    (141) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-8-((테트라하이드로-2H-피란-4-일)메틸)-7,8-디하이드로프테리딘-6(5H)-온;(141) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-7, 8-dihydropteridin-6(5H)-one;
    (142) 5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-8-((테트라하이드로-2H-피란-4-일)메틸)-7,8-디하이드로프테리딘-6(5H)-온;(142) 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridine -6(5H)-one;
    (143) 2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5,7-디메틸-8-(테트라하이드로-2H-피란-4-일)-7,8-디하이드로프테리딘-6(5H)-온;(143) 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran-4-yl)-7,8 -dihydropteridin-6(5H)-one;
    (144) 8-사이클로헥실-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(144) 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6, 7-dione;
    (145) 8-사이클로헥실-5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(145) 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine -6,7-dione;
    (146) 8-사이클로헥실-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온;(146) 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ;
    (147) 8-사이클로헥실-5-메틸-2-((7-메틸-2,3-디하이드로벤조[b][1,4]디옥신-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(147) 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8-di hydropteridine-6,7-dione;
    (148) 8-사이클로헥실-5-메틸-2-((7-메틸퀴놀린-6-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(148) 8-cyclohexyl-5-methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione;
    (149) 8-사이클로펜틸-5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(149) 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6, 7-dione;
    (150) 8-사이클로펜틸-5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-5,8-디하이드로프테리딘-6,7-디온;(150) 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine -6,7-dione;
    (151) 8-사이클로펜틸-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온;(151) 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7-dione ;
    (152) 5-메틸-2-((6-메틸벤조[c][1,2,5]티아디아졸-5-일)아미노)-8-(2-옥사스피로[3.5]노난-7-일)-5,8-디하이드로프테리딘-6,7-디온;(152) 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(2-oxaspiro[3.5]nonane-7- yl)-5,8-dihydropteridine-6,7-dione;
    (153) 5-메틸-2-((6-메틸벤조[d][1,3]디옥솔-5-일)아미노)-8-(2-옥사스피로[3.5]노난-7-일)-5,8-디하이드로프테리딘-6,7-디온;(153) 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(2-oxaspiro[3.5]nonan-7-yl)- 5,8-dihydropteridine-6,7-dione;
    (154) 8-사이클로부틸-2-((2,5-디메틸벤조[d]티아졸-6-일)아미노)-5-메틸-5,8-디하이드로프테리딘-6,7-디온;(154) 8-cyclobutyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ;
    (155) 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온; 및(155) 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-5,8-di hydropteridine-6,7-dione; and
    (156) 8-사이클로펜틸-5-메틸-2-((4-메틸-6-(1-메틸-1H-이미다졸-4-일)피리딘-3-일)아미노)-5,8-디하이드로프테리딘-6,7-디온.(156) 8-cyclopentyl-5-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-5,8-di hydropteridine-6,7-dione.
  8. 제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 제 8 항에 있어서, 9. The method of claim 8,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군에서 선택된 어느 하나 이상인 것인, 암의 예방 또는 치료용 약학적 조성물.The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, auditory schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus Any one or more selected from the group consisting of cancer, a pharmaceutical composition for the prevention or treatment of cancer.
  10. 제 8 항에 있어서,9. The method of claim 8,
    상기 약학적 조성물은 방사선 요법과 병행하여 투여되는 것인, 암의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of cancer, which is administered in parallel with radiation therapy.
  11. 제 8 항에 있어서,9. The method of claim 8,
    상기 약학적 조성물은 알트레타민, 벤다무스틴, 부술판, 카르무스틴, 클로로암부실, 클로로메틴, 시클로포스파미드, 다카르바진, 이포스파미드, 임프로술판 토실레이트, 로무스틴, 멜팔란, 미토브로니톨, 미토락톨, 니무스틴, 라니무스틴, 테모졸로미드, 티오테파, 트레오술판, 메클로로에타민, 카르보퀴온, 아파지퀀, 포테무스틴, 글루포스파미드, 팔리포스파미드, 피포브로만, 트로포스파미드, 우라무스틴, 카르보플라틴, 시스플라틴, 에프타플라틴, 미리플라틴 히드레이트, 옥살리플라틴, 로바플라틴, 네다플라틴, 사트라플라틴, 에토포시드, 이리노테칸, 라족산, 소부족산, 암루비신, 비산트렌, 데시타빈, 미톡산트론, 프로카르바진, 트라벡테딘, 클로파라빈, 암사크린, 브로스탈리신, 픽산트론, 라로무스틴, 블레오마이신, 닥티노마이신, 독소루비신, 에피루비신, 이다루비신, 레바미솔, 밀테포신, 미토마이신 C, 로미데프신, 스트렙토조신, 발루비신, 지노스타틴, 조루비신, 다우누로비신, 플리카마이신, 아클라루비신, 페플로마이신, 피라루비신, 알파라딘, 211At, 213Bi, 225Ac 및 227Th으로 이루어진 군으로부터 선택된 적어도 하나의 추가적인 항종양 물질과 병행하여 투여되는 것인, 암의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition is altretamine, bendamustine, busulfan, carmustine, chloroambucil, chloromethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan , mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, threosulfan, mechloroethamine, carboquinone, apaziquin, potemustine, gluphosphamide, palfosfamide , pipobroman, trophosphamide, uramustine, carboplatin, cisplatin, eftaplatin, myriplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, satraplatin, etoposide, irinotecan, la Zoxic acid, Sobusan, Amrubicin, Bisantrene, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Cloparabine, Amsacrine, Brostalysin, Pixantrone, Laromustine, Bleomycin, Doc Tinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosin, mitomycin C, romidepsin, streptozocin, valrubicin, ginostatin, zorubicin, daunurobicin, plicamycin, aclarubicin Sin, peplomycin, pyrarubicin, alfaradin, 211 At, 213 Bi, 225 Ac and 227 Th will be administered in combination with at least one additional anti-tumor agent selected from the group consisting of, for the prevention or treatment of cancer pharmaceutical composition.
  12. 암의 치료 또는 예방에 사용하기 위한 약제의 제조에 사용하기 위한, 제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도.Use of a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of cancer.
  13. 제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 암을 치료 또는 예방하는 방법.Claims 1 to 7, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. How to treat or prevent.
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